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Parveen S, Fatma M, Mir SS, Dermime S, Uddin S. JAK-STAT Signaling in Autoimmunity and Cancer. Immunotargets Ther 2025; 14:523-554. [PMID: 40376194 PMCID: PMC12080488 DOI: 10.2147/itt.s485670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 04/29/2025] [Indexed: 05/18/2025] Open
Abstract
The JAK-STAT pathway is an essential cell survival signaling that regulates gene expressions related to inflammation, immunity and cancer. Cytokine receptors, signal transducer and activator of transcription (STAT) proteins, and Janus kinases (JAKs) are the critical component of this signaling cascade. When JAKs are stimulated by cytokines, STAT phosphorylation, dimerization, and nuclear translocation occur, which eventually impacts gene transcription. Dysregulation of JAK-STAT signaling is linked with various autoimmune diseases, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. This pathway is constitutively activated in human malignancies and leads to tumor cell survival, proliferation, and immune evasion. Oncogenic mutations in the JAK and STAT genes have been found in solid tumors, leukemia, and lymphoma. Targeting the JAK-STAT pathway is a viable and promising therapeutic strategy for the treatment of autoimmune diseases and cancers.
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Affiliation(s)
- Sana Parveen
- Department of Biosciences, Faculty of Science, Integral University, Lucknow, India
- Molecular Cell Biology Laboratory, Integral Centre of Excellence for Interdisciplinary Research-4 (ICEIR-4) Integral University, Lucknow, India
| | - Mariyam Fatma
- Department of Biosciences, Faculty of Science, Integral University, Lucknow, India
- Molecular Cell Biology Laboratory, Integral Centre of Excellence for Interdisciplinary Research-4 (ICEIR-4) Integral University, Lucknow, India
| | - Snober Shabnam Mir
- Department of Biosciences, Faculty of Science, Integral University, Lucknow, India
- Molecular Cell Biology Laboratory, Integral Centre of Excellence for Interdisciplinary Research-4 (ICEIR-4) Integral University, Lucknow, India
| | - Said Dermime
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, 3050, Qatar
- College of Health Sciences, Qatar University, Doha, Qatar
| | - Shahab Uddin
- Department of Biosciences, Faculty of Science, Integral University, Lucknow, India
- Translational Research Institute & Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Laboratory Animal Research Center, Qatar University, Doha, Qatar
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Li Y, Pan AP, Ye Y, Shao X, Tu R, Liu Y, Yu AY. FoxO1 promotes high glucose-induced inflammation and cataract formation via JAK1/STAT1. Graefes Arch Clin Exp Ophthalmol 2025:10.1007/s00417-025-06744-6. [PMID: 39878886 DOI: 10.1007/s00417-025-06744-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 12/29/2024] [Accepted: 01/14/2025] [Indexed: 01/31/2025] Open
Abstract
PURPOSE To investigate whether in diabetic cataract (DC), FoxO1 regulates high glucose (HG)-induced activation of NLRC4/IL-6 inflammatory mediators in human lens epithelial cells (SRA01/04) via the JAK1/STAT1 pathway, leading to cataract formation. METHODS Expression levels of FoxO1, inflammatory factor IL-6 and inflammatory vesicle NLRC4 were examined in SRA01/04 under high glucose (HG) stress at 25-150 mM. Rat lenses were also cultured using HG medium with or without the addition of the FoxO1 inhibitor AS1842856 and the JAK1 agonist RO8191. 5.5 mM glucose concentration group (NG) was used as a control. Real-time PCR, Western blots, and immunofluorescent staining evaluated the mRNA and protein levels of FoxO1, NLRC4, and IL-6. Apoptosis, cell viability, and EDU Staining were also assessed. RESULTS HG stimulation induced elevated FoxO1 expression and caused NLRC4/IL-6 activation in a concentration-dependent manner. Whereas knockdown of FoxO1 inhibited the high expression of NLRC4/IL-6 inflammatory mediators in response to HG stimulation. The growth of SRA01/04 was inhibited under HG condition, and the cell proliferation ability was restored and even promoted by knocking out FoxO1. HG incubation of rat lens resulted in lens clouding and cataract formation, which was prevented by AS1842856 treatment and reversed by RO8191. CONCLUSION FoxO1 positively regulates HG-induced SRA01/04 inflammatory activation through the JAK1/STAT1 pathway and promotes DC. This provides a feasible strategy for the treatment of diabetic cataract.
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Affiliation(s)
- Yike Li
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, 270 Xueyuan West Road, Wenzhou, 325027, Zhejiang, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- Department of Ophthalmology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Chengguan District, Lanzhou, 730000, Gansu, People's Republic of China
| | - An-Peng Pan
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, 270 Xueyuan West Road, Wenzhou, 325027, Zhejiang, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yishan Ye
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, 270 Xueyuan West Road, Wenzhou, 325027, Zhejiang, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xu Shao
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, 270 Xueyuan West Road, Wenzhou, 325027, Zhejiang, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Ruixue Tu
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, 270 Xueyuan West Road, Wenzhou, 325027, Zhejiang, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yang Liu
- Department of Ophthalmology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Chengguan District, Lanzhou, 730000, Gansu, People's Republic of China
| | - A-Yong Yu
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, 270 Xueyuan West Road, Wenzhou, 325027, Zhejiang, China.
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
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Mukherjee A, Anoop C, Nongthomba U. What a tangled web we weave: crosstalk between JAK-STAT and other signalling pathways during development in Drosophila. FEBS J 2025. [PMID: 39821459 DOI: 10.1111/febs.17391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 09/26/2024] [Accepted: 12/23/2024] [Indexed: 01/19/2025]
Abstract
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway is a key player in animal development and physiology. Although it functions in a variety of processes, the net output of JAK-STAT signalling depends on its spatiotemporal activation, as well as extensive crosstalk with other signalling pathways. Drosophila, with its relatively simple signal transduction pathways and plethora of genetic analysis tools, is an ideal system for dissecting JAK-STAT signalling interactions. In this review, we explore studies in Drosophila revealing that JAK-STAT signalling lies at the nexus of a complex network of interlinked pathways, including epidermal growth factor receptor (EGFR), c-Jun N-terminal kinase (JNK), Notch, Insulin, Hippo, bone morphogenetic protein (BMP), Hedgehog (Hh) and Wingless (Wg). These pathways can synergise with or antagonise one another to produce a variety of outcomes. Given the conserved nature of signal transduction pathways, we conclude with our perspective on the implication of JAK-STAT signalling dysregulation in human diseases, and how studies in Drosophila have the potential to inform and influence clinical research.
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Affiliation(s)
- Amartya Mukherjee
- Department of Developmental Biology and Genetics, Indian Institute of Science (IISc), Bangalore, India
| | - Chaithra Anoop
- Department of Biological Science, Indian Institute of Science Education and Research (IISER), Mohali, India
| | - Upendra Nongthomba
- Department of Developmental Biology and Genetics, Indian Institute of Science (IISc), Bangalore, India
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Maji L, Sengupta S, Purawarga Matada GS, Teli G, Biswas G, Das PK, Panduranga Mudgal M. Medicinal chemistry perspective of JAK inhibitors: synthesis, biological profile, selectivity, and structure activity relationship. Mol Divers 2024; 28:4467-4513. [PMID: 38236444 DOI: 10.1007/s11030-023-10794-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 12/07/2023] [Indexed: 01/19/2024]
Abstract
JAK-STAT signalling pathway was discovered more than quarter century ago. The JAK-STAT pathway protein is considered as one of the crucial hubs for cytokine secretion which mediates activation of different inflammatory, cellular responses and hence involved in different etiological factors. The various etiological factors involved are haematopoiesis, immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis. The presence of the active mutation V617K plays a significant role in the progression of the JAK-STAT pathway-related disease. Consequently, targeting the JAK-STAT pathway could be a promising therapeutic approach for addressing a range of causative factors. In this current review, we provided a comprehensive discussion for the in-detail study of anatomy and physiology of the JAK-STAT pathway which contributes structural domain rearrangement, activation, and negative regulation associated with the downstream signaling pathway, relationship between different cytokines and diseases. This review also discussed the recent development of clinical trial entities. Additionally, this review also provides updates on FDA-approved drugs. In the current investigation, we have classified recently developed small molecule inhibitors of JAK-STAT pathway according to different chemical classes and we emphasized their synthetic routes, biological evaluation, selectivity, and structure-activity relationship.
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Affiliation(s)
- Lalmohan Maji
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, Karnataka, India
| | - Sindhuja Sengupta
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, Karnataka, India
| | | | - Ghanshyam Teli
- School of Pharmacy, Sangam University, Atoon, Bhilwara, 311001, Rajasthan, India
| | - Gourab Biswas
- Department of Pharmaceutical Technology, Brainware University, Kolkata, West Bengal, India
| | - Pronoy Kanti Das
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, Karnataka, India
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He Y, Shen M, Wang X, Yin A, Liu B, Zhu J, Zhang Z. Suppression of Interferon Response and Antiviral Strategies of Bunyaviruses. Trop Med Infect Dis 2024; 9:205. [PMID: 39330894 PMCID: PMC11435552 DOI: 10.3390/tropicalmed9090205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/28/2024] [Accepted: 09/05/2024] [Indexed: 09/28/2024] Open
Abstract
The order Bunyavirales belongs to the class of Ellioviricetes and is classified into fourteen families. Some species of the order Bunyavirales pose potential threats to human health. The continuously increasing research reveals that various viruses within this order achieve immune evasion in the host through suppressing interferon (IFN) response. As the types and nodes of the interferon response pathway are continually updated or enriched, the IFN suppression mechanisms and target points of different virus species within this order are also constantly enriched and exhibit variations. For instance, Puumala virus (PUUV) and Tula virus (TULV) can inhibit IFN response through their functional NSs inhibiting downstream factor IRF3 activity. Nevertheless, the IFN suppression mechanisms of Dabie bandavirus (DBV) and Guertu virus (GTV) are mostly mediated by viral inclusion bodies (IBs) or filamentous structures (FSs). Currently, there are no effective drugs against several viruses belonging to this order that pose significant threats to society and human health. While the discovery, development, and application of antiviral drugs constitute a lengthy process, our focus on key targets in the IFN response suppression process of the virus leads to potential antiviral strategies, which provide references for both basic research and practical applications.
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Affiliation(s)
- Yingying He
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
- Department of Clinical Medicine, Anhui Medical University, Hefei 230032, China
| | - Min Shen
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
- Department of Clinical Medicine, Anhui Medical University, Hefei 230032, China
| | - Xiaohe Wang
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
- Department of Clinical Medicine, Anhui Medical University, Hefei 230032, China
| | - Anqi Yin
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
- Department of Clinical Medicine, Anhui Medical University, Hefei 230032, China
| | - Bingyan Liu
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
| | - Jie Zhu
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
| | - Zhenhua Zhang
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; (Y.H.); (M.S.); (X.W.); (A.Y.); (B.L.)
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Tong Z, Zou JP, Wang SY, Luo WW, Wang YY. Activation of the cGAS-STING-IRF3 Axis by Type I and II Interferons Contributes to Host Defense. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308890. [PMID: 39004913 PMCID: PMC11425201 DOI: 10.1002/advs.202308890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 06/08/2024] [Indexed: 07/16/2024]
Abstract
Interferons (IFNs) activate JAK-STAT pathways to induce downstream effector genes for host defense against invaded pathogens and tumors. Here both type I (β) and II (γ) IFNs are shown that can activate the transcription factor IRF3 in parallel with STAT1. IRF3-deficiency impairs transcription of a subset of downstream effector genes induced by IFN-β and IFN-γ. Mechanistically, IFN-induced activation of IRF3 is dependent on the cGAS-STING-TBK1 axis. Both IFN-β and IFN-γ cause mitochondrial DNA release into the cytosol. In addition, IFNs induce JAK1-mediated tyrosine phosphorylation of cGAS at Y214/Y215, which is essential for its DNA binding activity and signaling. Furthermore, deficiency of cGAS, STING, or IRF3 impairs IFN-β- or IFN-γ-mediated antiviral and antitumor activities. The findings reveal a novel IRF3 activation pathway parallel with the canonical STAT1/2 activation pathways triggered by IFNs and provide an explanation for the pleiotropic roles of the cGAS-STING-IRF3 axis in host defense.
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Affiliation(s)
- Zhen Tong
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Bejing, 100049, China
| | - Jia-Peng Zou
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Bejing, 100049, China
| | - Su-Yun Wang
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Wei-Wei Luo
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Bejing, 100049, China
- Hubei Jiangxia Laboratory, Wuhan, Hubei, 430200, China
| | - Yan-Yi Wang
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China
- University of Chinese Academy of Sciences, Bejing, 100049, China
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Yan M, Sun Z, Zhang S, Yang G, Jiang X, Wang G, Li R, Wang Q, Tian X. SOCS modulates JAK-STAT pathway as a novel target to mediate the occurrence of neuroinflammation: Molecular details and treatment options. Brain Res Bull 2024; 213:110988. [PMID: 38805766 DOI: 10.1016/j.brainresbull.2024.110988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/28/2024] [Accepted: 05/26/2024] [Indexed: 05/30/2024]
Abstract
SOCS (Suppressor of Cytokine Signalling) proteins are intracellular negative regulators that primarily modulate and inhibit cytokine-mediated signal transduction, playing a crucial role in immune homeostasis and related inflammatory diseases. SOCS act as inhibitors by regulating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, thereby intervening in the pathogenesis of inflammation and autoimmune diseases. Recent studies have also demonstrated their involvement in central immunity and neuroinflammation, showing a dual functionality. However, the specific mechanisms of SOCS in the central nervous system remain unclear. This review thoroughly elucidates the specific mechanisms linking the SOCS-JAK-STAT pathway with the inflammatory manifestations of neurodegenerative diseases. Based on this, it proposes the theory that SOCS proteins can regulate the JAK-STAT pathway and inhibit the occurrence of neuroinflammation. Additionally, this review explores in detail the current therapeutic landscape and potential of targeting SOCS in the brain via the JAK-STAT pathway for neuroinflammation, offering insights into potential targets for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Min Yan
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Zhiyuan Sun
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Sen Zhang
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Guangxin Yang
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Xing Jiang
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Guilong Wang
- College of Graduate Education, Shandong Sport University, Jinan 255300, China
| | - Ran Li
- College of Graduate Education, Shandong Sport University, Jinan 255300, China.
| | - Qinglu Wang
- College of Graduate Education, Shandong Sport University, Jinan 255300, China.
| | - Xuewen Tian
- College of Graduate Education, Shandong Sport University, Jinan 255300, China.
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Bodega-Mayor I, Delgado-Wicke P, Arrabal A, Alegría-Carrasco E, Nicolao-Gómez A, Jaén-Castaño M, Espadas C, Dopazo A, de Luis EV, Martín-Gayo E, Gaspar ML, de Andrés B, Fernández-Ruiz E. Tyrosine kinase 2 modulates splenic B cells through type I IFN and TLR7 signaling. Cell Mol Life Sci 2024; 81:199. [PMID: 38683377 PMCID: PMC11058799 DOI: 10.1007/s00018-024-05234-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 01/29/2024] [Accepted: 04/05/2024] [Indexed: 05/01/2024]
Abstract
Tyrosine kinase 2 (TYK2) is involved in type I interferon (IFN-I) signaling through IFN receptor 1 (IFNAR1). This signaling pathway is crucial in the early antiviral response and remains incompletely understood on B cells. Therefore, to understand the role of TYK2 in B cells, we studied these cells under homeostatic conditions and following in vitro activation using Tyk2-deficient (Tyk2-/-) mice. Splenic B cell subpopulations were altered in Tyk2-/- compared to wild type (WT) mice. Marginal zone (MZ) cells were decreased and aged B cells (ABC) were increased, whereas follicular (FO) cells remained unchanged. Likewise, there was an imbalance in transitional B cells in juvenile Tyk2-/- mice. RNA sequencing analysis of adult MZ and FO cells isolated from Tyk2-/- and WT mice in homeostasis revealed altered expression of IFN-I and Toll-like receptor 7 (TLR7) signaling pathway genes. Flow cytometry assays corroborated a lower expression of TLR7 in MZ B cells from Tyk2-/- mice. Splenic B cell cultures showed reduced proliferation and differentiation responses after activation with TLR7 ligands in Tyk2-/- compared to WT mice, with a similar response to lipopolysaccharide (LPS) or anti-CD40 + IL-4. IgM, IgG, IL-10 and IL-6 secretion was also decreased in Tyk2-/- B cell cultures. This reduced response of the TLR7 pathway in Tyk2-/- mice was partially restored by IFNα addition. In conclusion, there is a crosstalk between TYK2 and TLR7 mediated by an IFN-I feedback loop, which contributes to the establishment of MZ B cells and to B cell proliferation and differentiation.
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Affiliation(s)
- Irene Bodega-Mayor
- Molecular Biology Unit, Hospital Universitario de La Princesa and Research Institute (IIS-Princesa), Madrid, Spain
- Immunobiology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Pablo Delgado-Wicke
- Molecular Biology Unit, Hospital Universitario de La Princesa and Research Institute (IIS-Princesa), Madrid, Spain
| | - Alejandro Arrabal
- Molecular Biology Unit, Hospital Universitario de La Princesa and Research Institute (IIS-Princesa), Madrid, Spain
- Immunobiology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Estíbaliz Alegría-Carrasco
- Molecular Biology Unit, Hospital Universitario de La Princesa and Research Institute (IIS-Princesa), Madrid, Spain
| | - Ana Nicolao-Gómez
- Molecular Biology Unit, Hospital Universitario de La Princesa and Research Institute (IIS-Princesa), Madrid, Spain
| | - Marta Jaén-Castaño
- Molecular Biology Unit, Hospital Universitario de La Princesa and Research Institute (IIS-Princesa), Madrid, Spain
| | - Cristina Espadas
- Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Ana Dopazo
- Genomics Unit, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Enrique Vázquez de Luis
- Immunology Department, Hospital Universitario de La Princesa and IIS-Princesa, Madrid, Spain
| | - Enrique Martín-Gayo
- Immunology Department, Hospital Universitario de La Princesa and IIS-Princesa, Madrid, Spain
- Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - María Luisa Gaspar
- Immunobiology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Belén de Andrés
- Immunobiology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Elena Fernández-Ruiz
- Molecular Biology Unit, Hospital Universitario de La Princesa and Research Institute (IIS-Princesa), Madrid, Spain.
- Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
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Wlassits R, Müller M, Fenzl KH, Lamprecht T, Erlacher L. JAK-Inhibitors - A Story of Success and Adverse Events. Open Access Rheumatol 2024; 16:43-53. [PMID: 38435420 PMCID: PMC10906274 DOI: 10.2147/oarrr.s436637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 02/17/2024] [Indexed: 03/05/2024] Open
Abstract
Rheumatoid arthritis (RA) is a systemic, chronic, immune-mediated inflammatory condition. Treatments options encompass conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic disease-modifying antirheumatic drugs (bDMARDs) like tumor necrosis factor (TNF) inhibitors (TNFis) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) including Janus Kinase inhibitors (JAKinibs). Orally administered JAKinibs have demonstrated comparable or, in specific cases, superior efficacy compared to bDMARDs in inflammatory conditions. However, the escalating clinical utilization has been accompanied by the emergence of serious adverse effects, including major adverse cardiac events (MACE), malignancies and venous thrombotic episodes (VTE), leading to regulatory restrictions imposed by health authorities in both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
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Affiliation(s)
- Rebekka Wlassits
- Karl Landsteiner Institut für Autoimmunerkrankungen und Rheumatologie, Vienna, Austria
| | - Mathias Müller
- Department für Biomedizinische Wissenschaften, Institut für Tierzucht und Genetik, Veterinärmedizinische Universität Wien, Vienna, Austria
| | - Karl H Fenzl
- Karl Landsteiner Institut für Autoimmunerkrankungen und Rheumatologie, Vienna, Austria
| | - Thomas Lamprecht
- Ludwig Erlacher, Karl Landsteiner Institut für Autoimmunerkrankungen und Rheumatologie, Vienna, Austria
| | - Ludwig Erlacher
- Ludwig Erlacher, Karl Landsteiner Institut für Autoimmunerkrankungen und Rheumatologie, Vienna, Austria
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Wang X, Yuan Z, Li Z, He X, Zhang Y, Wang X, Su J, Wu X, Li M, Du F, Chen Y, Deng S, Zhao Y, Shen J, Yi T, Xiao Z. Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances. Front Immunol 2024; 15:1354313. [PMID: 38426090 PMCID: PMC10902128 DOI: 10.3389/fimmu.2024.1354313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/29/2024] [Indexed: 03/02/2024] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. The treatment of HCC has witnessed a significant surge in recent years, with the emergence of targeted immune therapy as an adjunct to early surgical resection. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown promising results in other types of solid tumors. This article aims to provide a comprehensive overview of the intricate interactions between different types of TILs and their impact on HCC, elucidate strategies for targeting neoantigens through TILs, and address the challenges encountered in TIL therapies along with potential solutions. Furthermore, this article specifically examines the impact of oncogenic signaling pathways activation within the HCC tumor microenvironment on the infiltration dynamics of TILs. Additionally, a concise overview is provided regarding TIL preparation techniques and an update on clinical trials investigating TIL-based immunotherapy in solid tumors.
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Affiliation(s)
- Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zijun Yuan
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhengbo Li
- Department of Laboratory Medicine, The Longmatan District People’s Hospital, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Shuai Deng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Tao Yi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
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11
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Xu R, Lee YJ, Kim CH, Min GH, Kim YB, Park JW, Kim DH, Kim JH, Yim H. Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1. J Exp Clin Cancer Res 2023; 42:302. [PMID: 37968723 PMCID: PMC10652615 DOI: 10.1186/s13046-023-02872-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 10/26/2023] [Indexed: 11/17/2023] Open
Abstract
BACKGROUND Understanding the mechanism behind immune cell plasticity in cancer metastasis is crucial for identifying key regulators. Previously we found that mitotic factors regulate epithelial-mesenchymal transition, but how these factors convert to metastatic players in the tumor microenvironment (TME) is not fully understood. METHODS The clinical importance of mitotic factors was analyzed by heatmap analysis, a KM plot, and immunohistochemistry in lung adenocarcinoma (LUAD) patients. Immunoprecipitation, LC-MS/MS, kinase assay, and site-directed mutagenesis were performed for the interaction and phosphorylation. A tail-vein injection mouse model, Transwell-based 3D culture, microarray analysis, coculture with monocytes, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated FoxM1 in metastasis of TME. RESULTS The phosphorylated FoxM1 at Ser25 by PLK1 acquires the reprogramming ability to stimulate the invasive traits in cancer and influence immune cell plasticity. This invasive form of p-FoxM1 upregulates the expression of IL1A/1B, VEGFA, and IL6 by direct activation, recruiting monocytes and promoting the polarization of M2d-like tumor-associated macrophages (TAMs). Upregulation of PD-L1 in LUAD having phosphomimetic FoxM1 facilitates immune evasion. In invasive LUAD with phosphomimetic FoxM1, IFITM1 is the most highly expressed through the activation of the STING-TBK1-IRF3 signaling, which enhances FoxM1-mediated signaling. Clinically, higher expression of FOXM1, PLK1, and IFITM1 is inversely correlated with the survival rate of advanced LUAD patients, providing a promising therapeutic strategy for the treatment of LUAD. CONCLUSION FoxM1-based therapy would be a potential therapeutic strategy for LUAD to reduce TAM polarization, immune escape, and metastasis, since FoxM1 functions as a genetic reprogramming factor reinforcing LUAD malignancy in the TME.
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Affiliation(s)
- Rong Xu
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Young-Joo Lee
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Chang-Hyeon Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Ga-Hong Min
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Yeo-Bin Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Jung-Won Park
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Dae-Hoon Kim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea
| | - Jung-Hyun Kim
- Division of Intractable Diseases Research, Department of Chronic Diseases Convergence Research, Korea National Institute of Health, Cheongju, Chungcheongbuk-Do, 28160, Republic of Korea
| | - Hyungshin Yim
- Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-Do, 15588, Republic of Korea.
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12
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Lažetić V, Batachari LE, Russell AB, Troemel ER. Similarities in the induction of the intracellular pathogen response in Caenorhabditis elegans and the type I interferon response in mammals. Bioessays 2023; 45:e2300097. [PMID: 37667453 PMCID: PMC10694843 DOI: 10.1002/bies.202300097] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 09/06/2023]
Abstract
Although the type-I interferon (IFN-I) response is considered vertebrate-specific, recent findings about the Intracellular Pathogen Response (IPR) in nematode Caenorhabditis elegans indicate that there are similarities between these two transcriptional immunological programs. The IPR is induced during infection with natural intracellular fungal and viral pathogens of the intestine and promotes resistance against these pathogens. Similarly, the IFN-I response is induced by viruses and other intracellular pathogens and promotes resistance against infection. Whether the IPR and the IFN-I response evolved in a divergent or convergent manner is an unanswered and exciting question, which could be addressed by further studies of immunity against intracellular pathogens in C. elegans and other simple host organisms. Here we highlight similar roles played by RIG-I-like receptors, purine metabolism enzymes, proteotoxic stressors, and transcription factors to induce the IPR and IFN-I response, as well as the similar consequences of these defense programs on organismal development.
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Affiliation(s)
- Vladimir Lažetić
- School of Biological SciencesUniversity of California, San DiegoLa JollaCaliforniaUSA
- Department of Biological SciencesThe George Washington UniversityWashingtonDCUSA
| | - Lakshmi E. Batachari
- School of Biological SciencesUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Alistair B. Russell
- School of Biological SciencesUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Emily R. Troemel
- School of Biological SciencesUniversity of California, San DiegoLa JollaCaliforniaUSA
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13
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Mesev EV, Lin AE, Guare EG, Heller BL, Douam F, Adamson B, Toettcher JE, Ploss A. Membrane-proximal motifs encode differences in signaling strength between type I and III interferon receptors. Sci Signal 2023; 16:eadf5494. [PMID: 37816090 PMCID: PMC10939449 DOI: 10.1126/scisignal.adf5494] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 09/09/2023] [Indexed: 10/12/2023]
Abstract
Interferons (IFNs) play crucial roles in antiviral defenses. Despite using the same Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) signaling cascade, type I and III IFN receptors differ in the magnitude and dynamics of their signaling in terms of STAT phosphorylation, gene transcription, and antiviral responses. These differences are not due to ligand-binding affinity and receptor abundance. Here, we investigated the ability of the intracellular domains (ICDs) of IFN receptors to differentiate between type I and III IFN signaling. We engineered synthetic, heterodimeric type I and III IFN receptors that were stably expressed at similar amounts in human cells and responded to a common ligand. We found that our synthetic type I IFN receptors stimulated STAT phosphorylation and gene expression to greater extents than did the corresponding type III IFN receptors. Furthermore, we identified short "box motifs" within ICDs that bind to JAK1 that were sufficient to encode differences between the type I and III IFN receptors. Together, our results indicate that specific regions within the ICDs of IFN receptor subunits encode different downstream signaling strengths that enable type I and III IFN receptors to produce distinct signaling outcomes.
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Affiliation(s)
- Emily V. Mesev
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Aaron E. Lin
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Emma G. Guare
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Brigitte L. Heller
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Florian Douam
- Department of Microbiology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
- National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA
| | - Britt Adamson
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
- Lewis Sigler Center for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
| | - Jared E. Toettcher
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
- Omenn-Darling Bioengineering Institute, Princeton University, Princeton, NJ 08544, USA
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
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14
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Coscarella G, Malvaso D, Mannino M, Caldarola G, Fossati B, De Simone C, Chiricozzi A, Peris K. The preclinical discovery and development of deucravacitinib for the treatment of psoriasis. Expert Opin Drug Discov 2023; 18:1201-1208. [PMID: 37574849 DOI: 10.1080/17460441.2023.2246880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 08/08/2023] [Indexed: 08/15/2023]
Abstract
INTRODUCTION Psoriasis is a chronic inflammatory skin disease that most commonly presents as plaque psoriasis. The understanding of the pivotal pathogenetic role of the IL-23/IL-17 axis has dramatically changed the therapeutic approach to the disease. The identification of intracellular signaling pathways mediating IL-23 activity provided the rationale for targeting TYK2. AREAS COVERED This review assesses the underlying rationale that led to development of deucravacitinib, a novel oral TYK2 inhibitor, as a therapeutic option for the treatment of moderate-to-severe psoriasis, primarily focusing on pre-clinical and early phase clinical studies. EXPERT OPINION Innovative therapies used in patients with moderate-to-severe psoriasis include biologic agents and small molecules, which are associated with less adverse events than traditional systemic agents. Deucravacitinib, which selectively targets TYK2, has demonstrated to be effective in treating psoriasis, preserving a more favorable safety profile compared to other JAK inhibitors approved for the treatment of other immune diseases that block the ATP-binding site. Because of its oral administration, deucravacitinib represents an intriguing option in the therapeutic armamentarium of psoriasis, though the evaluation of long-term efficacy and safety is necessary to establish its place-in-therapy.
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Affiliation(s)
- Giulia Coscarella
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy
| | - Dalma Malvaso
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maria Mannino
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy
| | - Giacomo Caldarola
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy
| | - Barbara Fossati
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy
| | - Clara De Simone
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy
| | - Andrea Chiricozzi
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy
| | - Ketty Peris
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy
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15
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Valle-Mendiola A, Gutiérrez-Hoya A, Soto-Cruz I. JAK/STAT Signaling and Cervical Cancer: From the Cell Surface to the Nucleus. Genes (Basel) 2023; 14:1141. [PMID: 37372319 DOI: 10.3390/genes14061141] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/13/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway constitutes a rapid signaling module from the cell surface to the nucleus, and activates different cellular responses, such as proliferation, survival, migration, invasion, and inflammation. When the JAK/STAT pathway is altered, it contributes to cancer progression and metastasis. STAT proteins play a central role in developing cervical cancer, and inhibiting the JAK/STAT signaling may be necessary to induce tumor cell death. Several cancers show continuous activation of different STATs, including cervical cancer. The constitutive activation of STAT proteins is associated with a poor prognosis and overall survival. The human papillomavirus (HPV) oncoproteins E6 and E7 play an essential role in cervical cancer progression, and they activate the JAK/STAT pathway and other signals that induce proliferation, survival, and migration of cancer cells. Moreover, there is a crosstalk between the JAK/STAT signaling cascade with other signaling pathways, where a plethora of different proteins activate to induce gene transcription and cell responses that contribute to tumor growth. Therefore, inhibition of the JAK/STAT pathway shows promise as a new target in cancer treatment. In this review, we discuss the role of the JAK/STAT pathway components and the role of the HPV oncoproteins associated with cellular malignancy through the JAK/STAT proteins and other signaling pathways to induce tumor growth.
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Affiliation(s)
- Arturo Valle-Mendiola
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, FES Zaragoza, National University of Mexico, Batalla 5 de Mayo s/n, Colonia Ejército de Oriente, Mexico City 09230, Mexico
| | - Adriana Gutiérrez-Hoya
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, FES Zaragoza, National University of Mexico, Batalla 5 de Mayo s/n, Colonia Ejército de Oriente, Mexico City 09230, Mexico
- Cátedra CONACYT, FES Zaragoza, National University of Mexico, Mexico City 09230, Mexico
| | - Isabel Soto-Cruz
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, FES Zaragoza, National University of Mexico, Batalla 5 de Mayo s/n, Colonia Ejército de Oriente, Mexico City 09230, Mexico
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16
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Ott N, Faletti L, Heeg M, Andreani V, Grimbacher B. JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences. J Clin Immunol 2023:10.1007/s10875-023-01483-x. [PMID: 37140667 DOI: 10.1007/s10875-023-01483-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 04/01/2023] [Indexed: 05/05/2023]
Abstract
The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathway's architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases.
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Affiliation(s)
- Nils Ott
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Laura Faletti
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Maximilian Heeg
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Division of Biological Sciences, Department of Molecular Biology, University of California, La Jolla, San Diego, CA, USA
| | - Virginia Andreani
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bodo Grimbacher
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- DZIF - German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany
- CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany
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17
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Sun Q, Zhang J, Wang J, Wang H, Gao Z, Liu H. Janus kinase 1 in Megalobrama amblycephala: Identification, phylogenetic analysis and expression profiling after Aeromonas hydrophila infection. FISH & SHELLFISH IMMUNOLOGY 2023; 135:108620. [PMID: 36841516 DOI: 10.1016/j.fsi.2023.108620] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/07/2023] [Accepted: 02/15/2023] [Indexed: 06/18/2023]
Abstract
Janus kinase 1 (JAK1), a member of the JAK family, plays an essential and non-redundant role in the mammalian immune system. However, the potential role of JAK1 in fish immune response remains largely unclear. In the present study, the JAK1 gene of Megalobrama amblycephala (MamJAK1) was identified and characterized. The open reading frame (ORF) of MamJAK1 was 3462 bp, encoding 1153 amino acids. MamJAK1 consists of four common domains of the JAK family, including B41, SH2, STyrKc (a pseudo kinase domain), and TyrKc (a kinase domain). Phylogenetic analysis showed that JAK1s are divided into two evolutionary clades, one containing fish JAK1s, and the other containing JAK1s from other vertebrates. The results of quantitative real-time PCR (qPCR) showed that in healthy M. amblycephala, MamJAK1 mRNA was highest expressed in blood, followed by spleen, intestine and mid-kidney, and lowly expressed in other tissues including gill, liver, head kidney, muscle, brain and heart. After Aeromonas hydrophila infection, the expression of MamJAK1 mRNA was significantly induced in four selected tissues including spleen, mid-kidney, liver and intestine, reaching a peak at 24 hpi (hour post infection) in spleen and mid-kidney, at 12 hpi in liver and at 4 hpi in intestine, and then the expression level was restricted to control levels at 72 or 120 hpi. In addition, the results of Western blot showed that the phosphorylation level of MamJAK1 protein in spleen and mid-kidney increased significantly after A. hydrophila infection, although MamJAK1 protein did not change obviously. Further, the JAK1 phosphorylation in Ctenopharyngodon idellus kidney (CIK) cells was found to be significantly induced by LPS stimulation and IL-6R over-expression. The results above suggest that MamJAK1 may play an essential role in the immune response against bacterial infection through the IL-6R mediated JAK1/STAT signaling pathway, which further deepen our understanding of JAK1 and provides a potential target for the treatment and prevention of bacterial diseases in teleost.
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Affiliation(s)
- Qianhui Sun
- College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture and Rural Affair / Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education / Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Jian Zhang
- College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture and Rural Affair / Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education / Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Jixiu Wang
- College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture and Rural Affair / Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education / Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Huanling Wang
- College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture and Rural Affair / Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education / Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Zexia Gao
- College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture and Rural Affair / Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education / Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China
| | - Hong Liu
- College of Fisheries, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture and Rural Affair / Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education / Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China; Hubei Hongshan Laboratory, Wuhan, 430070, China.
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18
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Chow RD, Michaels T, Bellone S, Hartwich TM, Bonazzoli E, Iwasaki A, Song E, Santin AD. Distinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti-PD-1 Immunotherapy in Endometrial Carcinoma. Cancer Discov 2023; 13:312-331. [PMID: 36301137 PMCID: PMC9905265 DOI: 10.1158/2159-8290.cd-22-0686] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/29/2022] [Accepted: 10/19/2022] [Indexed: 02/07/2023]
Abstract
Mismatch repair-deficient (MMRd) cancers have varied responses to immune-checkpoint blockade (ICB). We conducted a phase II clinical trial of the PD-1 inhibitor pembrolizumab in 24 patients with MMRd endometrial cancer (NCT02899793). Patients with mutational MMRd tumors (6 patients) had higher response rates and longer survival than those with epigenetic MMRd tumors (18 patients). Mutation burden was higher in tumors with mutational MMRd compared with epigenetic MMRd; however, within each category of MMRd, mutation burden was not correlated with ICB response. Pretreatment JAK1 mutations were not associated with primary resistance to pembrolizumab. Longitudinal single-cell RNA-seq of circulating immune cells revealed contrasting modes of antitumor immunity for mutational versus epigenetic MMRd cancers. Whereas effector CD8+ T cells correlated with regression of mutational MMRd tumors, activated CD16+ NK cells were associated with ICB-responsive epigenetic MMRd tumors. These data highlight the interplay between tumor-intrinsic and tumor-extrinsic factors that influence ICB response. SIGNIFICANCE The molecular mechanism of MMRd is associated with response to anti-PD-1 immunotherapy in endometrial carcinoma. Tumors with epigenetic MMRd or mutational MMRd are correlated with NK cell or CD8+ T cell-driven immunity, respectively. Classifying tumors by the mechanism of MMRd may inform clinical decision-making regarding cancer immunotherapy. This article is highlighted in the In This Issue feature, p. 247.
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Affiliation(s)
- Ryan D. Chow
- Department of Genetics, Yale University, New Haven, Connecticut, USA
- System Biology Institute, Yale University, West Haven, Connecticut, USA
- Corresponding authors: Correspondence to: Ryan D. Chow, Address: 850 West Campus Drive, ISTC 314, West Haven CT 06516, , Phone: 203-737-3825, Eric Song, Address: 300 Cedar Street, Suite S630, New Haven, CT 06519, , Phone: 203-785-2919, Alessandro D. Santin, Address: 333 Cedar Street, PO Box 208063, New Haven, CT 06511, , Phone: 203-737-2280
| | - Tai Michaels
- Department of Immunobiology, Yale University, New Haven, Connecticut, USA
| | - Stefania Bellone
- Smilow Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Tobias M.P. Hartwich
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Elena Bonazzoli
- Smilow Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Akiko Iwasaki
- Department of Immunobiology, Yale University, New Haven, Connecticut, USA
- Howard Hughes Medical Institute, Yale University, New Haven, Connecticut, USA
| | - Eric Song
- Department of Immunobiology, Yale University, New Haven, Connecticut, USA
- Corresponding authors: Correspondence to: Ryan D. Chow, Address: 850 West Campus Drive, ISTC 314, West Haven CT 06516, , Phone: 203-737-3825, Eric Song, Address: 300 Cedar Street, Suite S630, New Haven, CT 06519, , Phone: 203-785-2919, Alessandro D. Santin, Address: 333 Cedar Street, PO Box 208063, New Haven, CT 06511, , Phone: 203-737-2280
| | - Alessandro D. Santin
- Smilow Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA
- Corresponding authors: Correspondence to: Ryan D. Chow, Address: 850 West Campus Drive, ISTC 314, West Haven CT 06516, , Phone: 203-737-3825, Eric Song, Address: 300 Cedar Street, Suite S630, New Haven, CT 06519, , Phone: 203-785-2919, Alessandro D. Santin, Address: 333 Cedar Street, PO Box 208063, New Haven, CT 06511, , Phone: 203-737-2280
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19
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Efficacy and Safety of JAK1 Inhibitor Abrocitinib in Atopic Dermatitis. Pharmaceutics 2023; 15:pharmaceutics15020385. [PMID: 36839707 PMCID: PMC9960033 DOI: 10.3390/pharmaceutics15020385] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 01/24/2023] Open
Abstract
Abrocitinib is a JAK1 selective inhibitor recently approved for the treatment of moderate-to-severe atopic dermatitis in adults. It has demonstrated efficacy and safety in several clinical trials, both in children and adults, in monotherapy, and compared with dupilumab. The expected EASI-75 response rate estimates at week 12 are 62.9% (95% CrI 42.5-79.9%) for abrocitinib 200 mg and 43.0% (95% CrI 24.8-64.0%) for abrocitinib 100 mg. Abrocitinib has shown a faster effect than dupilumab as regards early alleviation of itch. Because of the incomplete target selectivity of JAK inhibitors, when abrocitinib treatment is considered, laboratory screening is necessary, latent tuberculosis must be screened for, active infections are a contraindication, and special caution must be exerted in treating elderly patients and those predisposed to thromboembolic events. Even though recent meta-analyses of clinical trials have not shown that atopic dermatitis, or its treatment with JAK inhibitors or dupilumab, modify the risk of deep venous thrombosis or pulmonary embolism, long-term follow-up studies will better define the safety profile of abrocitinib.
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20
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The Role of the JAK/STAT Signaling Pathway in the Pathogenesis of Alzheimer's Disease: New Potential Treatment Target. Int J Mol Sci 2023; 24:ijms24010864. [PMID: 36614305 PMCID: PMC9821184 DOI: 10.3390/ijms24010864] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/19/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023] Open
Abstract
Alzheimer's disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, emerging evidence suggests that neuroinflammation, mediated notably by activated neuroglial cells, neutrophils, and macrophages, also plays an important role in the pathogenesis of Alzheimer's disease. Therefore, understanding the interplay between the nervous and immune systems might be the key to the prevention or delay of Alzheimer's disease progression. One of the most important mechanisms determining gliogenic cell fate is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway that is influenced by the overactivation of microglia and astrocytes. The JAK/STAT signaling pathway is one of the critical factors that promote neuroinflammation in neurodegenerative diseases such as Alzheimer's disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and finally, constraining neuroinflammatory response. Since a chronic neuroinflammatory environment in the brain is a hallmark of Alzheimer's disease, understanding the process would allow establishing the underlying role of neuroinflammation, then estimating the prognosis of Alzheimer's disease development and finding a new potential treatment target. In this review, we highlight the recent advances in the potential role of JAK/STAT signaling in neurological diseases with a focus on discussing future research directions regarding novel therapeutic approaches and predictive biomarkers for Alzheimer's disease.
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21
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Liu Y, Zhai G, Fu W, Zhang X, Xu J. A randomized, double-blind, placebo-controlled phase I trial of inhalation treatment of recombinant TFF2-IFN protein: A multifunctional candidate for the treatment of COVID-19. Front Pharmacol 2022; 13:1063106. [PMID: 36578554 PMCID: PMC9790930 DOI: 10.3389/fphar.2022.1063106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022] Open
Abstract
Background and Objectives: Coronavirus disease 2019 (COVID-19) has caused global pandemics in the last 3 years, and the development of new therapeutics is urgently needed. This study aimed to assess the safety, tolerated, and prolonged retention of recombinant protein trefoil factor 2 (TFF2)- interferon (IFN) in the respiratory tract of healthy volunteers. Methods: We conducted a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase I study to evaluate safety, tolerability, pharmacokinetics (PK), and cytokine responses after administration of recombinant TFF2-IFN proteins. Healthy volunteers were informed, enrolled, and randomized into four groups with a dose escalation of 0.2, 1, 2, and 4 mg and then inhaled the investigation product or placebo. Thirty-two eligible participants were finally enrolled; eight were assigned to the placebo group and 24 to the TFF2-IFN group, with six participants per group. Data were collected from 19 November 2021, to 4 January 2022. Results: All 32 participants completed the study. Of the participants who received the recombinant TFF2-IFN protein, 41.7% (10/24) reported 11 adverse events (AEs) during treatment and 62.5% (5/8) of those who received a placebo reported six AEs. Sixteen of the 17 AEs were grade 1. Only one grade 3 AE occurred in the placebo group and no worse event occurred as a serious adverse event. The pharmacokinetics was analyzed for times and concentrations of the investigation products in 0.2, 1, 2, and 4 mg groups in 24 recipients of TFF2-IFN, and the results showed that TFF2-IFN was retained in the lung for at least 6-8 h. Only the highest dose group (4 mg) had a transient detectable concentration in serum, while all other dose groups had a level below the lower limit of quantification. Conclusion: In this study, the recombinant TFF2-IFN protein was a well-tolerated and safe therapeutic when administered by nebulization, characterized by prolonged retention in the respiratory tract, which would be greatly beneficial in combating respiratory viral infection. Systematic Review Registration: [http://www.chictr.org.cn], identifier [ChiCTR2000035633].
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Affiliation(s)
- Yan Liu
- Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China,National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guanxing Zhai
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Weihui Fu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xiaoyan Zhang
- Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China,Shanghai Public Health Clinical Center, Fudan University, Shanghai, China,*Correspondence: Xiaoyan Zhang, ; Jianqing Xu,
| | - Jianqing Xu
- Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China,Shanghai Public Health Clinical Center, Fudan University, Shanghai, China,*Correspondence: Xiaoyan Zhang, ; Jianqing Xu,
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22
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Bisom TC, White LA, Lanchy JM, Lodmell JS. RIOK3 and Its Alternatively Spliced Isoform Have Disparate Roles in the Innate Immune Response to Rift Valley Fever Virus (MP12) Infection. Viruses 2022; 14:2064. [PMID: 36146870 PMCID: PMC9502082 DOI: 10.3390/v14092064] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 09/15/2022] [Accepted: 09/15/2022] [Indexed: 12/14/2022] Open
Abstract
Rift Valley fever virus (RVFV) is a pathogenic human and livestock RNA virus that poses a significant threat to public health and biosecurity. During RVFV infection, the atypical kinase RIOK3 plays important roles in the innate immune response. Although its exact functions in innate immunity are not completely understood, RIOK3 has been shown to be necessary for mounting an antiviral interferon (IFN) response to RVFV in epithelial cells. Furthermore, after immune stimulation, the splicing pattern for RIOK3 mRNA changes markedly, and RIOK3's dominant alternatively spliced isoform, RIOK3 X2, exhibits an opposite effect on the IFN response by dampening it. Here, we further investigate the roles of RIOK3 and its spliced isoform in other innate immune responses to RVFV, namely the NFκB-mediated inflammatory response. We find that while RIOK3 is important for negatively regulating this inflammatory pathway, its alternatively spliced isoform, RIOK3 X2, stimulates it. Overall, these data demonstrate that both RIOK3 and its X2 isoform have unique roles in separate innate immune pathways that respond to RVFV infection.
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Affiliation(s)
- Thomas C. Bisom
- Department of Chemistry and Biochemistry, University of Montana, Missoula, MT 59801, USA
| | - Luke A. White
- Division of Biological Sciences, University of Montana, Missoula, MT 59801, USA
| | - Jean-Marc Lanchy
- Division of Biological Sciences, University of Montana, Missoula, MT 59801, USA
| | - J. Stephen Lodmell
- Division of Biological Sciences, University of Montana, Missoula, MT 59801, USA
- Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT 59801, USA
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23
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Jiang B, Wang J, Liu W, Cheng J, Xu J, Cao M, Li Y. Comparative transcriptome analysis of MDBK cells reveals that BoIFN-γ augmented host immune responses to bovine herpesvirus 1 infection. Front Microbiol 2022; 13:973278. [PMID: 36016774 PMCID: PMC9396027 DOI: 10.3389/fmicb.2022.973278] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Bovine herpesvirus 1 (BoHV-1) is an alphaherpesvirus that causes infectious bovine rhinotracheitis and infectious pustular vulvovaginitis in cattle. Ιnterferon-gamma (IFN-γ) is a pleiotropic cytokine with antiviral activity that modulates the innate and adaptive immune responses. In this study, we prepared high-purity bovine interferon gamma (BoIFN-γ) dimer protein using prokaryotic expression system and affinity chromatography. We subsequently investigated the effect of BoIFN-γ on BoHV-1 infection in Madin-Darby bovine kidney (MDBK) cells. The results showed that BoIFN-γ pre-treament not only decreased the production of BoHV-1 but also reduced the cytopathic effect of the virus. Differential gene expression profiles of BoHV-1 infected MDBK cells were then analysed through high-throughput RNA sequencing. The data showed that BoIFN-γ pre-treatment reduced lipid metabolism disorder and DNA damage caused by BoHV-1 infection. Furthermore, BoIFN-γ treatment upregulated the transcription of interferon regulatory transcription factors (IRF1 and GBP5) and interferon-stimulated genes (ISGs) of MDBK cells. Additionally, BoIFN-γ promotes expression of cellular protein involved in complement activation and coagulation cascades response as well as antigen processing and presentation process, while BoHV-1 infection dramatically downregulates transcription of these immune components including C3, C1r, C1s, PLAT, ITGB2, PROCR, BoLA, CD74, B2M, PA28, BoLA-DRA, and TAPBP. Collectively, our findings revealed that BoIFN-γ pre-treatment can improve host resistance to BoHV-1 infection and regulate transcription or expression of host protein associated with cellular metabolism and innate immune response. This provides insights into the development of prophylactic agents for prevention and control of BoHV-1 infection.
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Affiliation(s)
- Bo Jiang
- Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agricultural and Forestry Sciences, Beijing, China
| | - Jing Wang
- Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agricultural and Forestry Sciences, Beijing, China
| | - Wenxiao Liu
- Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agricultural and Forestry Sciences, Beijing, China
| | - Jing Cheng
- Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agricultural and Forestry Sciences, Beijing, China
| | - Jian Xu
- Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Mengyao Cao
- Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agricultural and Forestry Sciences, Beijing, China
- Animal Science and Technology College, Beijing University of Agriculture, Beijing, China
| | - Yongqing Li
- Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agricultural and Forestry Sciences, Beijing, China
- *Correspondence: Yongqing Li,
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24
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Tehlirian C, Singh RSP, Pradhan V, Roberts ES, Tarabar S, Peeva E, Vincent MS, Gale JD. Oral tyrosine kinase 2 inhibitor PF-06826647 demonstrates efficacy and an acceptable safety profile in participants with moderate-to-severe plaque psoriasis in a phase 2b, randomized, double-blind, placebo-controlled study. J Am Acad Dermatol 2022; 87:333-342. [DOI: 10.1016/j.jaad.2022.03.059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/25/2022] [Accepted: 03/29/2022] [Indexed: 10/18/2022]
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25
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Fleischmann R. Recent issues in JAK inhibitor safety: perspective for the clinician. Expert Rev Clin Immunol 2022; 18:295-307. [DOI: 10.1080/1744666x.2022.2039122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Roy Fleischmann
- Clinical Professor of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Co-Medical Director, Metroplex Clinical Research Center, 8144 Walnut Hill Lane, Suite 810, Dallas 75231, Texas,USA
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26
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Muromoto R, Oritani K, Matsuda T. Current understanding of the role of tyrosine kinase 2 signaling in immune responses. World J Biol Chem 2022; 13:1-14. [PMID: 35126866 PMCID: PMC8790287 DOI: 10.4331/wjbc.v13.i1.1] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 08/06/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Immune system is a complex network that clears pathogens, toxic substrates, and cancer cells. Distinguishing self-antigens from non-self-antigens is critical for the immune cell-mediated response against foreign antigens. The innate immune system elicits an early-phase response to various stimuli, whereas the adaptive immune response is tailored to previously encountered antigens. During immune responses, B cells differentiate into antibody-secreting cells, while naïve T cells differentiate into functionally specific effector cells [T helper 1 (Th1), Th2, Th17, and regulatory T cells]. However, enhanced or prolonged immune responses can result in autoimmune disorders, which are characterized by lymphocyte-mediated immune responses against self-antigens. Signal transduction of cytokines, which regulate the inflammatory cascades, is dependent on the members of the Janus family of protein kinases. Tyrosine kinase 2 (Tyk2) is associated with receptor subunits of immune-related cytokines, such as type I interferon, interleukin (IL)-6, IL-10, IL-12, and IL-23. Clinical studies on the therapeutic effects and the underlying mechanisms of Tyk2 inhibitors in autoimmune or chronic inflammatory diseases are currently ongoing. This review summarizes the findings of studies examining the role of Tyk2 in immune and/or inflammatory responses using Tyk2-deficient cells and mice.
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Affiliation(s)
- Ryuta Muromoto
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Kenji Oritani
- Department of Hematology, International University of Health and Welfare, Narita 286-8686, Japan
| | - Tadashi Matsuda
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
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27
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White LA, Bisom TC, Grimes HL, Hayashi M, Lanchy JM, Lodmell JS. Tra2beta-Dependent Regulation of RIO Kinase 3 Splicing During Rift Valley Fever Virus Infection Underscores the Links Between Alternative Splicing and Innate Antiviral Immunity. Front Cell Infect Microbiol 2022; 11:799024. [PMID: 35127560 PMCID: PMC8807687 DOI: 10.3389/fcimb.2021.799024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022] Open
Abstract
Rift Valley fever virus (RVFV) is an emerging pathogen that has potential to cause severe disease in humans and domestic livestock. Propagation of RVFV strain MP-12 is negatively impacted by the actions of RIOK3, a protein involved in the cellular immune response to viral infection. During RVFV infection, RIOK3 mRNA is alternatively spliced to produce an isoform that correlates with the inhibition of interferon β signaling. Here, we identify splicing factor TRA2-β (also known as TRA2beta and hTRA2-β) as a key regulator governing the relative abundance of RIOK3 splicing isoforms. Using RT-PCR and minigenes, we determined that TRA2-β interaction with RIOK3 pre-mRNA was necessary for constitutive splicing of RIOK3 mRNA, and conversely, lack of TRA2-β engagement led to increased alternative splicing. Expression of TRA2-β was found to be necessary for RIOK3's antiviral effect against RVFV. Intriguingly, TRA2-β mRNA is also alternatively spliced during RVFV infection, leading to a decrease in cellular TRA2-β protein levels. These results suggest that splicing modulation serves as an immune evasion strategy by RVFV and/or is a cellular mechanism to prevent excessive immune response. Furthermore, the results suggest that TRA2-β can act as a key regulator of additional steps of the innate immune response to viral infection.
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Affiliation(s)
- Luke Adam White
- Division of Biological Sciences, University of Montana, Missoula, MT, United States
| | - Thomas C. Bisom
- Department of Chemistry and Biochemistry, University of Montana, Missoula, MT, United States
| | - Hunter L. Grimes
- Division of Biological Sciences, University of Montana, Missoula, MT, United States
| | - Miyuki Hayashi
- Department of Chemistry and Biochemistry, University of Montana, Missoula, MT, United States
| | - Jean-Marc Lanchy
- Division of Biological Sciences, University of Montana, Missoula, MT, United States
| | - J. Stephen Lodmell
- Division of Biological Sciences, University of Montana, Missoula, MT, United States
- Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT, United States
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28
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Dowling JW, Forero A. Beyond Good and Evil: Molecular Mechanisms of Type I and III IFN Functions. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:247-256. [PMID: 35017214 DOI: 10.4049/jimmunol.2100707] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/11/2021] [Indexed: 12/24/2022]
Abstract
IFNs are comprised of three families of cytokines that confer protection against pathogen infection and uncontrolled cellular proliferation. The broad role IFNs play in innate and adaptive immune regulation has placed them under heavy scrutiny to position them as "friend" or "foe" across pathologies. Genetic lesions in genes involving IFN synthesis and signaling underscore the disparate outcomes of aberrant IFN signaling. Abrogation of the response leads to susceptibility to microbial infections whereas unabated IFN induction underlies a variety of inflammatory diseases and tumor immune evasion. Type I and III IFNs have overlapping roles in antiviral protection, yet the mechanisms by which they are induced and promote the expression of IFN-stimulated genes and inflammation can distinguish their biological functions. In this review, we examine the molecular factors that shape the shared and distinct roles of type I and III IFNs in immunity.
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Affiliation(s)
- Jack W Dowling
- Biochemistry, College of Arts and Sciences, The Ohio State University, Columbus, OH 43210; and.,Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210
| | - Adriana Forero
- Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210
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29
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Cattaneo D, Iurlo A. Immune Dysregulation and Infectious Complications in MPN Patients Treated With JAK Inhibitors. Front Immunol 2021; 12:750346. [PMID: 34867980 PMCID: PMC8639501 DOI: 10.3389/fimmu.2021.750346] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022] Open
Abstract
BCR-ABL1-negative myeloproliferative neoplasms are burdened by a reduced life expectancy mostly due to an increased risk of thrombo-hemorrhagic events, fibrotic progression/leukemic evolution, and infectious complications. In these clonal myeloid malignancies, JAK2V617F is the main driver mutation, leading to an aberrant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Therefore, its inhibition represents an attractive therapeutic strategy for these disorders. Several JAK inhibitors have entered clinical trials, including ruxolitinib, the first JAK1/2 inhibitor to become commercially available for the treatment of myelofibrosis and polycythemia vera. Due to interference with the JAK-STAT pathway, JAK inhibitors affect several components of the innate and adaptive immune systems such as dendritic cells, natural killer cells, T helper cells, and regulatory T cells. Therefore, even though the clinical use of these drugs in MPN patients has led to a dramatic improvement of symptoms control, organ involvement, and quality of life, JAK inhibitors–related loss of function in JAK-STAT signaling pathway can be a cause of different adverse events, including those related to a condition of immune suppression or deficiency. This review article will provide a comprehensive overview of the current knowledge on JAK inhibitors’ effects on immune cells as well as their clinical consequences, particularly with regards to infectious complications.
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Affiliation(s)
- Daniele Cattaneo
- Hematology Division, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Alessandra Iurlo
- Hematology Division, Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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30
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Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther 2021; 6:402. [PMID: 34824210 PMCID: PMC8617206 DOI: 10.1038/s41392-021-00791-1] [Citation(s) in RCA: 1208] [Impact Index Per Article: 302.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 09/09/2021] [Accepted: 09/21/2021] [Indexed: 02/08/2023] Open
Abstract
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.
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Affiliation(s)
- Xiaoyi Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, 610041, Chengdu, P. R. China
| | - Jing Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China
| | - Maorong Fu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China
| | - Xia Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China.
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, 610041, Chengdu, P. R. China.
| | - Wei Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, 610041, Sichuan, P. R. China.
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31
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Duncan CJA, Hambleton S. Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy. J Clin Immunol 2021; 41:1446-1456. [PMID: 34448086 PMCID: PMC8390117 DOI: 10.1007/s10875-021-01118-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 08/03/2021] [Indexed: 12/28/2022]
Abstract
STAT2 is distinguished from other STAT family members by its exclusive involvement in type I and III interferon (IFN-I/III) signaling pathways, and its unique behavior as both positive and negative regulator of IFN-I signaling. The clinical relevance of these opposing STAT2 functions is exemplified by monogenic diseases of STAT2. Autosomal recessive STAT2 deficiency results in heightened susceptibility to severe and/or recurrent viral disease, whereas homozygous missense substitution of the STAT2-R148 residue is associated with severe type I interferonopathy due to loss of STAT2 negative regulation. Here we review the clinical presentation, pathogenesis, and management of these disorders of STAT2.
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Affiliation(s)
- Christopher James Arthur Duncan
- Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
- Royal Victoria Infirmary, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, NE1 4LP, Newcastle upon Tyne, UK.
| | - Sophie Hambleton
- Translational and Clinical Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
- Great North Children's Hospital, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, NE1 4LP, Newcastle upon Tyne, UK
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Lodhi N, Singh R, Rajput SP, Saquib Q. SARS-CoV-2: Understanding the Transcriptional Regulation of ACE2 and TMPRSS2 and the Role of Single Nucleotide Polymorphism (SNP) at Codon 72 of p53 in the Innate Immune Response against Virus Infection. Int J Mol Sci 2021; 22:8660. [PMID: 34445373 PMCID: PMC8395432 DOI: 10.3390/ijms22168660] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 07/28/2021] [Accepted: 08/02/2021] [Indexed: 12/15/2022] Open
Abstract
Human ACE2 and the serine protease TMPRSS2 of novel SARS-CoV-2 are primary entry receptors in host cells. Expression of these genes at the transcriptional level has not been much discussed in detail. The ISRE elements of the ACE2 promoter are a binding site for the ISGF3 complex of the JAK/STAT signaling pathway. TMPRSS2, including IFNβ, STAT1, and STAT2, has the PARP1 binding site near to TSS either up or downstream promoter region. It is well documented that PARP1 regulates gene expression at the transcription level. Therefore, to curb virus infection, both promoting type I IFN signaling to boost innate immunity and prevention of virus entry by inhibiting PARP1, ACE2 or TMPRSS2 are safe options. Most importantly, our aim is to attract the attention of the global scientific community towards the codon 72 Single Nucleotide Polymorphism (SNP) of p53 and its underneath role in the innate immune response against SARS-CoV-2. Here, we discuss codon 72 SNP of human p53's role in the different innate immune response to restrict virus-mediated mortality rate only in specific parts of the world. In addition, we discuss potential targets and emerging therapies using bioengineered bacteriophage, anti-sense, or CRISPR strategies.
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Affiliation(s)
- Niraj Lodhi
- Clinical Research (Research and Development Division) miRNA Analytics LLC, Harlem Bio-Space, New York, NY 10027, USA
| | - Rubi Singh
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA;
| | | | - Quaiser Saquib
- Department of Zoology, College of Sciences, King Saud University, Riyadh 12372, Saudi Arabia;
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Krueger JG, McInnes IB, Blauvelt A. Tyrosine kinase 2 and Janus kinase‒signal transducer and activator of transcription signaling and inhibition in plaque psoriasis. J Am Acad Dermatol 2021; 86:148-157. [PMID: 34224773 DOI: 10.1016/j.jaad.2021.06.869] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 06/01/2021] [Accepted: 06/23/2021] [Indexed: 01/14/2023]
Abstract
Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a major role in intracellular cytokine signaling in inflammatory processes involved in psoriasis. Although Janus kinase (JAK) 1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe psoriasis, safety concerns persist and no JAK inhibitor has received regulatory approval to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis. Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and regulates signaling and functional responses downstream of the interleukin 12, interleukin 23, and type I interferon receptors. Deucravacitinib, which is an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and PF-06826647, which are topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews Janus kinase-signal transducer and activator of transcription and TYK2 signaling and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors.
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Affiliation(s)
- James G Krueger
- Laboratory for Investigative Dermatology, Rockefeller University, New York, New York
| | - Iain B McInnes
- Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland
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Tavakoli Shirazi P, Eadie LN, Page EC, Heatley SL, Bruning JB, White DL. Constitutive JAK/STAT signaling is the primary mechanism of resistance to JAKi in TYK2-rearranged acute lymphoblastic leukemia. Cancer Lett 2021; 512:28-37. [PMID: 33971281 DOI: 10.1016/j.canlet.2021.04.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/14/2021] [Accepted: 04/29/2021] [Indexed: 12/26/2022]
Abstract
Activating TYK2-rearrangements have recently been identified and implicated in the leukemogenesis of high-risk acute lymphoblastic leukemia (HR-ALL) cases. Pre-clinical studies indicated the JAK/TYK2 inhibitor (JAKi), cerdulatinib, as a promising therapeutic against TYK2-rearranged ALL, attenuating the constitutive JAK/STAT signaling resulting from the TYK2 fusion protein. However, following a period of clinical efficacy, JAKi resistance often occurs resulting in relapse. In this study, we modeled potential mechanisms of JAKi resistance in TYK2-rearranged ALL cells in vitro in order to recapitulate possible clinical scenarios and provide a rationale for alternative therapies. Cerdulatinib resistant B-cells, driven by the MYB-TYK2 fusion oncogene, were generated by long-term exposure to the drug. Sustained treatment of MYB-TYK2-rearranged ALL cells with cerdulatinib led to enhanced and persistent JAK/STAT signaling, co-occurring with JAK1 overexpression. Hyperactivation of JAK/STAT signaling and JAK1 overexpression was reversible as cerdulatinib withdrawal resulted in re-sensitization to the drug. Importantly, histone deacetylase inhibitor (HDACi) therapies were efficacious against cerdulatinib-resistant cells demonstrating a potential alternative therapy for use in TYK2-rearranged B-ALL patients who have lost response to JAKi treatment regimens.
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Affiliation(s)
- Paniz Tavakoli Shirazi
- Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.
| | - Laura N Eadie
- Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.
| | - Elyse C Page
- Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia; Faculty of Sciences, University of Adelaide, Adelaide, Australia.
| | - Susan L Heatley
- Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.
| | - John B Bruning
- Faculty of Sciences, University of Adelaide, Adelaide, Australia.
| | - Deborah L White
- Cancer Program, Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia; Faculty of Sciences, University of Adelaide, Adelaide, Australia; Australian Genomics Health Alliance (AGHA), Australia.
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Kienes I, Weidl T, Mirza N, Chamaillard M, Kufer TA. Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation. Int J Mol Sci 2021; 22:1301. [PMID: 33525590 PMCID: PMC7865845 DOI: 10.3390/ijms22031301] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.
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Affiliation(s)
- Ioannis Kienes
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | - Tanja Weidl
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | - Nora Mirza
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | | | - Thomas A. Kufer
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
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Nakayama T, Yoshimura M, Higashioka K, Miyawaki K, Ota Y, Ayano M, Kimoto Y, Mitoma H, Ono N, Arinobu Y, Kikukawa M, Yamada H, Akashi K, Horiuchi T, Niiro H. Type 1 helper T cells generate CXCL9/10-producing T-bet + effector B cells potentially involved in the pathogenesis of rheumatoid arthritis. Cell Immunol 2020; 360:104263. [PMID: 33387686 DOI: 10.1016/j.cellimm.2020.104263] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 11/19/2020] [Accepted: 12/14/2020] [Indexed: 01/04/2023]
Abstract
Efficacy of B-cell depletion therapy highlights the antibody-independent effector functions of B cells in rheumatoid arthritis (RA). Given type 1 helper T (Th1) cells abundant in synovial fluid (SF) of RA, we have determined whether Th1 cells could generate novel effector B cells. Microarray and qPCR analysis identified CXCL9/10 transcripts as highly expressed genes upon BCR/CD40/IFN-γ stimulation. Activated Th1 cells promoted the generation of CXCL9/10-producing T-bet+ B cells. Expression of CXCL9/10 was most pronounced in CXCR3+ switched memory B cells. Compared with peripheral blood, SFRA enriched highly activated Th1 cells that coexisted with abundant CXCL9/10-producing T-bet+ B cells. Intriguingly, anti-IFN-γ antibody and JAK inhibitors significantly abrogated the generation of CXCL9/10-producing T-bet+ B cells. B cell derived CXCL9/10 significantly facilitated the migration of CD4+ T cells. These findings suggest that Th1 cells generate the novel CXCL9/10-producing T-bet+ effector B cells that could be an ideal pathogenic B cell target for RA therapy.
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Affiliation(s)
- Tsuyoshi Nakayama
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Motoki Yoshimura
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Kazuhiko Higashioka
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Kohta Miyawaki
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yuri Ota
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Masahiro Ayano
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yasutaka Kimoto
- Department of Internal Medicine and Clinical Immunology, Kyushu University Beppu Hospital, Beppu, Japan
| | - Hiroki Mitoma
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Nobuyuki Ono
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yojiro Arinobu
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Makoto Kikukawa
- Department of Medical Education, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Hisakata Yamada
- Department of Arthritis and Immunology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Takahiko Horiuchi
- Department of Internal Medicine and Clinical Immunology, Kyushu University Beppu Hospital, Beppu, Japan
| | - Hiroaki Niiro
- Department of Medical Education, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
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Gadina M, Chisolm DA, Philips RL, McInness IB, Changelian PS, O'Shea JJ. Translating JAKs to Jakinibs. THE JOURNAL OF IMMUNOLOGY 2020; 204:2011-2020. [PMID: 32253269 DOI: 10.4049/jimmunol.1901477] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/11/2020] [Indexed: 12/21/2022]
Abstract
The discovery of JAKs and STATs and their roles in cytokine and IFN action represented a significant basic advance and a new paradigm in cell signaling. This was quickly followed by discoveries pointing to their essential functions, including identification of JAK3 mutations as a cause of SCID. This and other findings predicted the use of therapeutically targeting JAKs as a new strategy for treating immune and inflammatory diseases. This now is a reality with seven approved jakinibs being used to treat multiple forms of arthritis, inflammatory bowel disease and myeloproliferative neoplasms, and numerous ongoing clinical trials in other settings. This story provides interesting insights into the process of translating basic discoveries and also reveals the need to return to basic work to fill gaps that now become apparent.
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Affiliation(s)
- Massimo Gadina
- Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Danielle A Chisolm
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Rachael L Philips
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Iain B McInness
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom; and
| | | | - John J O'Shea
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
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Nogueira M, Puig L, Torres T. JAK Inhibitors for Treatment of Psoriasis: Focus on Selective TYK2 Inhibitors. Drugs 2020; 80:341-352. [PMID: 32020553 DOI: 10.1007/s40265-020-01261-8] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Despite advances in the treatment of psoriasis, there is an unmet need for effective and safe oral treatments. The Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway plays a significant role in intracellular signalling of cytokines of numerous cellular processes, important in both normal and pathological states of immune-mediated inflammatory diseases. Particularly in psoriasis, where the interleukin (IL)-23/IL-17 axis is currently considered the crucial pathogenic pathway, blocking the JAK-STAT pathway with small molecules would be expected to be clinically effective. However, relative non-specificity and low therapeutic index of the available JAK inhibitors have delayed their integration into the therapeutic armamentarium of psoriasis. Current research appears to be focused on Tyrosine kinase 2 (TYK2), the first described member of the JAK family. Data from the Phase II trial of BMS-986165-a selective TYK2 inhibitor-in psoriasis have been published and clinical results are encouraging, with a large Phase III programme ongoing. Further, the selective TYK2 inhibitor PF-06826647 is being tested in moderate-to-severe psoriasis in a Phase II clinical trial. Brepocitinib, a potent TYK2/JAK1 inhibitor, is also being evaluated, as both oral and topical treatment. Results of studies with TYK2 inhibitors will be important in assessing the clinical efficacy and safety of these drugs and their place in the therapeutic armamentarium of psoriasis. This article reviews current data on the impact of JAK inhibitors in the treatment of adult patients with moderate-to-severe psoriasis.
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Affiliation(s)
- Miguel Nogueira
- Department of Dermatology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Luis Puig
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Tiago Torres
- Department of Dermatology, Centro Hospitalar Universitário do Porto, Porto, Portugal. .,Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.
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Xiao Y, Xu H, Guo W, Zhao Y, Luo Y, Wang M, He Z, Ding Z, Liu J, Deng L, Sha F, Ma X. Update on treatment and preventive interventions against COVID-19: an overview of potential pharmacological agents and vaccines. MOLECULAR BIOMEDICINE 2020; 1:16. [PMID: 34765999 PMCID: PMC7711057 DOI: 10.1186/s43556-020-00017-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 11/11/2020] [Indexed: 02/06/2023] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) triggered by the new member of the coronaviridae family, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created an unprecedented challenge for global health. In addition to mild to moderate clinical manifestations such as fever, cough, and fatigue, severe cases often developed lethal complications including acute respiratory distress syndrome (ARDS) and acute lung injury. Given the alarming rate of infection and increasing trend of mortality, the development of underlying therapeutic and preventive treatment, as well as the verification of its effectiveness, are the top priorities. Current research mainly referred to and evaluated the application of the empirical treatment based on two precedents, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), including antiviral drugs targeting different stages of virus replication, immunotherapy modulating the overactivated inflammation response, and other therapies such as herbal medicine and mesenchymal stem cells. Besides, the ongoing development of inventing prophylactic interventions such as various vaccines by companies and institutions worldwide is crucial to decline morbidity and mortality. This review mainly focused on promising candidates for the treatment of COVID-19 and collected recently updated evidence relevant to its feasibility in clinical practice in the near future.
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Affiliation(s)
- Yinan Xiao
- Department of Biotherapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041 China
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Hanyue Xu
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041 China
- West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Wen Guo
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, 610041 China
- West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Yunuo Zhao
- Department of Biotherapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041 China
- West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Yuling Luo
- Department of Biotherapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041 China
- West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Ming Wang
- Infectious Diseases Center, West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Zhiyao He
- Department of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041 China
| | - Zhenyu Ding
- Department of Biotherapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041 China
- West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Jiyan Liu
- Department of Biotherapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041 China
- West China Hospital, Sichuan University, Chengdu, 610041 China
| | - Lei Deng
- Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York, 10465 USA
| | - Fushen Sha
- Department of Internal Medicine, State University of New York, Downstate Medical Center, Brooklyn, New York, 11203 USA
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041 China
- West China Hospital, Sichuan University, Chengdu, 610041 China
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Crowley EL, Nezamololama N, Papp K, Gooderham MJ. Abrocitinib for the treatment of atopic dermatitis. Expert Rev Clin Immunol 2020; 16:955-962. [PMID: 32969750 DOI: 10.1080/1744666x.2021.1828068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Janus kinase (JAK) inhibitors are emerging treatments in dermatology. Also known as JAKinibs, these agents target JAK-signal transducers and activators of transcription (JAK-STAT) pathway for intracellular signaling. Among the various immune-mediated inflammatory skin diseases that the JAK-STAT pathway plays a role in, atopic dermatitis (AD) is an important one. AD has a complex and multifactorial pathophysiology that is not fully understood. Immune dysregulation can result in epidermal barrier disruption and intensify atopic dermatitis. The newly developed abrocitinib (PF-04965842) selectively inhibits the JAK1 protein, which is believed to modulate cytokines involved in AD pathophysiology. AREAS COVERED This work is a review of the current literature related to abrocitinib, including the phase I, II, and III clinical trials, for the treatment of AD. Immunological considerations of abrocitinib and JAK inhibition are also explored. EXPERT OPINION Abrocitinib is among the first JAK inhibitors evaluated for the treatment of AD. Similar to other JAKinhibs that mechanistically block the signaling of several cytokines, abrocitinib possesses both positive and negative clinical attributes. Nonetheless, the risk-benefit profile of abrocitinib remains favorable. Up to 61% of AD patients achieve an EASI 75 response while a minority of responding patients experience mild to moderate symptoms related to tolerability.
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Affiliation(s)
- Erika L Crowley
- International Space University , Illkirch-Graffenstaden, France
| | | | - Kim Papp
- Probity Medical Research , Waterloo, ON, Canada.,K Papp Clinical Research , Waterloo, ON, Canada
| | - Melinda J Gooderham
- Skin Centre for Dermatology , Peterborough, ON, Canada.,Probity Medical Research , Waterloo, ON, Canada.,Department of Medicine, Queen's University , Kingston, ON, Canada
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Nezamololama N, Crowley EL, Gooderham MJ, Papp K. Abrocitinib: a potential treatment for moderate-to-severe atopic dermatitis. Expert Opin Investig Drugs 2020; 29:911-917. [PMID: 32741227 DOI: 10.1080/13543784.2020.1804854] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Atopic dermatitis (AD) is a common and debilitating dermatosis that often impacts the physical and psychological quality of life in children and adults. A limited number of treatment options are available for AD, and often these treatments result in an insufficient response or may be contraindicated for some patients. This treatment gap creates an increasing demand for alternative AD therapies. The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway is known to play a critical role in the dysregulation of immune responses in AD. Inhibition of the JAK enzymes in the JAK-STAT pathway has shown potential for the treatment of this chronic skin condition. AREAS COVERED We review the evolving efficacy and safety profile of abrocitinib, an oral JAK1 inhibitor, in the treatment of AD based on the data available from phase I, II, and III clinical trials. EXPERT OPINION Evidence supports clinical efficacy, improved pruritus and an acceptable safety profile, making abrocitinib a viable alternative to conventional AD therapies. Pivotal phase III trials included subjects aged 12 years and above, providing a new mechanism of action for future treatment of adolescent and adult AD. Further investigations are required to have a thorough understanding of abrocitinib in the treatment of AD.
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Affiliation(s)
| | - Erika L Crowley
- Space Studies, International Space University , Illkirch-Graffenstaden, France
| | - Melinda J Gooderham
- Skin Centre for Dermatology , Peterborough, ON.,Department of Medicine, Queen's University , Kingston, ON.,Probity Medical Research , Waterloo, ON
| | - Kim Papp
- Probity Medical Research , Waterloo, ON.,K Papp Clinical Research , Waterloo, ON
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Ross SH, Cantrell DA. Of Mosaicism and Mechanisms: How JAK1 Goes Awry. Immunity 2020; 53:481-484. [PMID: 32937149 DOI: 10.1016/j.immuni.2020.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Personalized medicines require understanding the molecular causes of disease. In this issue of Immunity, Gruber et al. reveal that a gain-of-function JAK1 genetic variant results in a mutant protein with mosaic expression that drives multi-organ immune dysregulation via kinase dependent and independent mechanisms. The work highlights how biochemistry can inform therapies to resolve complex immune disorders.
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Affiliation(s)
- Sarah H Ross
- Lymphocyte Signaling and Development, The Babraham Institute, Cambridge CB22 3AT, UK
| | - Doreen A Cantrell
- Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
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43
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Garrido-Trigo A, Salas A. Molecular Structure and Function of Janus Kinases: Implications for the Development of Inhibitors. J Crohns Colitis 2020; 14:S713-S724. [PMID: 32083640 PMCID: PMC7395311 DOI: 10.1093/ecco-jcc/jjz206] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cytokines can trigger multiple signalling pathways, including Janus tyrosine kinases [JAK] and signal transducers and activators of transcription [STATS] pathways. JAKs are cytoplasmic proteins that, following the binding of cytokines to their receptors, transduce the signal by phosphorylating STAT proteins which enter the nuclei and rapidly target gene promoters to regulate gene transcription. Due to the critical involvement of JAK proteins in mediating innate and adaptive immune responses, these family of kinases have become desirable pharmacological targets in inflammatory diseases, including ulcerative colitis and Crohn's disease. In this review we provide an overview of the main cytokines that signal through the JAK/STAT pathway and the available in vivo evidence on mutant or deleted JAK proteins, and discuss the implications of pharmacologically targeting this kinase family in the context of inflammatory diseases.
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Affiliation(s)
- Alba Garrido-Trigo
- Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS] – CIBEREHD, Barcelona, Spain
| | - Azucena Salas
- Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS] – CIBEREHD, Barcelona, Spain,Corresponding author: Azucena Salas, PhD, Inflammatory Bowel Disease Unit, Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS] – CIBEREHD, Rosselló 149-153, Barcelona 08036, Spain.
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Metcalfe RD, Putoczki TL, Griffin MDW. Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11. Front Immunol 2020; 11:1424. [PMID: 32765502 PMCID: PMC7378365 DOI: 10.3389/fimmu.2020.01424] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 06/02/2020] [Indexed: 12/12/2022] Open
Abstract
Cytokines are small signaling proteins that have central roles in inflammation and cell survival. In the half-century since the discovery of the first cytokines, the interferons, over fifty cytokines have been identified. Amongst these is interleukin (IL)-6, the first and prototypical member of the IL-6 family of cytokines, nearly all of which utilize the common signaling receptor, gp130. In the last decade, there have been numerous advances in our understanding of the structural mechanisms of IL-6 family signaling, particularly for IL-6 itself. However, our understanding of the detailed structural mechanisms underlying signaling by most IL-6 family members remains limited. With the emergence of new roles for IL-6 family cytokines in disease and, in particular, roles of IL-11 in cardiovascular disease, lung disease, and cancer, there is an emerging need to develop therapeutics that can progress to clinical use. Here we outline our current knowledge of the structural mechanism of signaling by the IL-6 family of cytokines. We discuss how this knowledge allows us to understand the mechanism of action of currently available inhibitors targeting IL-6 family cytokine signaling, and most importantly how it allows for improved opportunities to pharmacologically disrupt cytokine signaling. We focus specifically on the need to develop and understand inhibitors that disrupt IL-11 signaling.
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Affiliation(s)
- Riley D Metcalfe
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Technology Institute, The University of Melbourne, Parkville, VIC, Australia
| | - Tracy L Putoczki
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Michael D W Griffin
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Technology Institute, The University of Melbourne, Parkville, VIC, Australia
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Gan LL, Hii LW, Wong SF, Leong CO, Mai CW. Molecular Mechanisms and Potential Therapeutic Reversal of Pancreatic Cancer-Induced Immune Evasion. Cancers (Basel) 2020; 12:1872. [PMID: 32664564 PMCID: PMC7408947 DOI: 10.3390/cancers12071872] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/06/2020] [Accepted: 07/09/2020] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer ranks high among the causes of cancer-related mortality. The prognosis of this grim condition has not improved significantly over the past 50 years, despite advancement in imaging techniques, cancer genetics and treatment modalities. Due to the relative difficulty in the early detection of pancreatic tumors, as low as 20% of patients are eligible for potentially curative surgery; moreover, chemotherapy and radiotherapy (RT) do not confer a great benefit in the overall survival of the patients. Currently, emerging developments in immunotherapy have yet to bring a significant clinical advantage among pancreatic cancer patients. In fact, pancreatic tumor-driven immune evasion possesses one of the greatest challenges leading to immunotherapeutic resistance. Most of the immune escape pathways are innate, while poor priming of hosts' immune response and immunoediting constitute the adaptive immunosuppressive machinery. In this review, we extensively discuss the pathway perturbations undermining the anti-tumor immunity specific to pancreatic cancer. We also explore feasible up-and-coming therapeutic strategies that may restore immunity and address therapeutic resistance, bringing hope to eliminate the status quo in pancreatic cancer prognosis.
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Affiliation(s)
- Li-Lian Gan
- School of Postgraduate Study, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-L.G.); (L.-W.H.)
| | - Ling-Wei Hii
- School of Postgraduate Study, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-L.G.); (L.-W.H.)
- School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
| | - Shew-Fung Wong
- School of Medicine, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
- Centre for Environmental and Population Health, Institute for Research, Development and Innovation (IRDI), International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Chee-Onn Leong
- School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
- Centre for Cancer and Stem Cells Research, Institute for Research, Development and Innovation (IRDI), International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Chun-Wai Mai
- School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
- Centre for Cancer and Stem Cells Research, Institute for Research, Development and Innovation (IRDI), International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, Malaysia
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Defective Influenza A Virus RNA Products Mediate MAVS-Dependent Upregulation of Human Leukocyte Antigen Class I Proteins. J Virol 2020; 94:JVI.00165-20. [PMID: 32321802 PMCID: PMC7307169 DOI: 10.1128/jvi.00165-20] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/16/2020] [Indexed: 01/14/2023] Open
Abstract
Human leukocyte antigens (HLAs) are cell surface proteins that regulate innate and adaptive immune responses to viral infection by engaging with receptors on immune cells. Many viruses have evolved ways to evade host immune responses by modulating HLA expression and/or processing. Here, we provide evidence that aberrant RNA products of influenza virus genome replication can trigger retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS)-dependent remodeling of the cell surface, increasing surface presentation of HLA proteins known to inhibit the activation of an immune cell known as a natural killer (NK) cell. While this HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein, which limits RIG-I activation and interferon production by the infected cell. Influenza A virus (IAV) increases the presentation of class I human leukocyte antigen (HLA) proteins that limit antiviral responses mediated by natural killer (NK) cells, but molecular mechanisms for these processes have not yet been fully elucidated. We observed that infection with A/Fort Monmouth/1/1947(H1N1) IAV significantly increased the presentation of HLA-B, -C, and -E on lung epithelial cells. Virus entry was not sufficient to induce HLA upregulation because UV-inactivated virus had no effect. Aberrant internally deleted viral RNAs (vRNAs) known as mini viral RNAs (mvRNAs) and defective interfering RNAs (DI RNAs) expressed from an IAV minireplicon were sufficient for inducing HLA upregulation. These defective RNAs bind to retinoic acid-inducible gene I (RIG-I) and initiate mitochondrial antiviral signaling (MAVS) protein-dependent antiviral interferon (IFN) responses. Indeed, MAVS was required for HLA upregulation in response to IAV infection or ectopic mvRNA/DI RNA expression. The effect was partially due to paracrine signaling, as we observed that IAV infection or mvRNA/DI RNA-expression stimulated production of IFN-β and IFN-λ1 and conditioned media from these cells elicited a modest increase in HLA surface levels in naive epithelial cells. HLA upregulation in response to aberrant viral RNAs could be prevented by the Janus kinase (JAK) inhibitor ruxolitinib. While HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein; we determined that NS1 limits cell-intrinsic and paracrine mechanisms of HLA upregulation. Taken together, our findings indicate that aberrant IAV RNAs stimulate HLA presentation, which may aid viral evasion of innate immunity. IMPORTANCE Human leukocyte antigens (HLAs) are cell surface proteins that regulate innate and adaptive immune responses to viral infection by engaging with receptors on immune cells. Many viruses have evolved ways to evade host immune responses by modulating HLA expression and/or processing. Here, we provide evidence that aberrant RNA products of influenza virus genome replication can trigger retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS)-dependent remodeling of the cell surface, increasing surface presentation of HLA proteins known to inhibit the activation of an immune cell known as a natural killer (NK) cell. While this HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein, which limits RIG-I activation and interferon production by the infected cell.
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Hamid AB, Petreaca RC. Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells. Cancers (Basel) 2020; 12:cancers12040927. [PMID: 32283832 PMCID: PMC7226513 DOI: 10.3390/cancers12040927] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/05/2020] [Accepted: 04/07/2020] [Indexed: 12/14/2022] Open
Abstract
Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.
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Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling. Nat Commun 2020; 11:1146. [PMID: 32123171 PMCID: PMC7052135 DOI: 10.1038/s41467-020-14948-z] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 02/10/2020] [Indexed: 12/15/2022] Open
Abstract
Linear ubiquitination is a critical regulator of inflammatory signaling pathways. However, linearly ubiquitinated substrates and the biological significance of linear ubiquitination is incompletely understood. Here, we show that STAT1 has linear ubiquitination at Lys511 and Lys652 residues in intact cells, which inhibits STAT1 binding to the type-I interferon receptor IFNAR2, thereby restricting STAT1 activation and resulting in type-I interferon signaling homeostasis. Linear ubiquitination of STAT1 is removed rapidly by OTULIN upon type-I interferon stimulation, which facilitates activation of interferon-STAT1 signaling. Furthermore, viruses induce HOIP expression through the NF-κB pathway, which in turn increases linear ubiquitination of STAT1 and thereby inhibits interferon antiviral response. Consequently, HOIL-1L heterozygous mice have active STAT1 signaling and enhanced responses to type-I interferons. These findings demonstrate a linear ubiquitination-mediated switch between homeostasis and activation of type-I interferon signaling, and suggest potential strategies for clinical antiviral therapy.
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Abdeldayem A, Raouf YS, Constantinescu SN, Moriggl R, Gunning PT. Advances in covalent kinase inhibitors. Chem Soc Rev 2020; 49:2617-2687. [DOI: 10.1039/c9cs00720b] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
This comprehensive review details recent advances, challenges and innovations in covalent kinase inhibition within a 10 year period (2007–2018).
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Affiliation(s)
- Ayah Abdeldayem
- Department of Chemical & Physical Sciences
- University of Toronto
- Mississauga
- Canada
- Department of Chemistry
| | - Yasir S. Raouf
- Department of Chemical & Physical Sciences
- University of Toronto
- Mississauga
- Canada
- Department of Chemistry
| | | | - Richard Moriggl
- Institute of Animal Breeding and Genetics
- University of Veterinary Medicine
- 1210 Vienna
- Austria
| | - Patrick T. Gunning
- Department of Chemical & Physical Sciences
- University of Toronto
- Mississauga
- Canada
- Department of Chemistry
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Sun Y, Shi H, Hong Z, Chi P. Inhibition of JAK1 mitigates postoperative ileus in mice. Surgery 2019; 166:1048-1054. [DOI: 10.1016/j.surg.2019.07.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 07/02/2019] [Accepted: 07/22/2019] [Indexed: 12/31/2022]
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