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1
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Saito K, Fujimoto M, Funajima E, Serada S, Ohkawara T, Ishihara M, Yamada M, Suzuki H, Miya F, Kosaki K, Fujieda M, Naka T. Novel germline STAT3 gain-of-function mutation causes autoimmune diseases and severe growth failure. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. GLOBAL 2024; 3:100312. [PMID: 39253104 PMCID: PMC11381862 DOI: 10.1016/j.jacig.2024.100312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 04/29/2024] [Accepted: 05/16/2024] [Indexed: 09/11/2024]
Abstract
Background In recent years, germline gain-of-function (GOF) mutations in signal transducer and activator of transcription 3 (STAT3) have been identified as a cause of early-onset multiorgan autoimmune diseases with the widespread use of next-generation sequencing, and targeted therapies such as tocilizumab have been reported to be effective. Objective We sought to assess whether a novel STAT3 mutation detected by whole-exome sequencing is pathogenic and examine the efficacy of targeted therapy. Methods A pediatric patient with idiopathic pulmonary hemosiderosis, autoimmune thyroiditis, inflammatory bowel disease unclassified, leukocytosis, thrombocytosis, and severe growth failure was examined. Results This 7-year-old boy had idiopathic pulmonary hemosiderosis at the age of 6 months. Despite high-dose steroid therapy, pulmonary fibrosis progressed. Furthermore, he presented with severe growth failure, autoimmune thyroiditis, leukocytosis, thrombocytosis, and inflammation bowel disease unclassified. Given the presence of multiple autoimmune diseases, whole-exome sequencing was performed, which detected germline de novo heterozygous STAT3 mutation (NM_139276.2; c.2144C>A, p.(P715Q)). Dual-luciferase reporter assay revealed this novel STAT3 mutation as GOF. After starting tocilizumab therapy at the age of 6, hospital stays decreased, and the progression of pulmonary fibrosis was decelerated without increasing the steroid dose. New autoimmune diseases did not develop, and no apparent adverse effects on growth have been observed. Conclusions Tocilizumab may be effective for patients with STAT3 GOF mutation, including those requiring long-term management of idiopathic pulmonary hemosiderosis. Diagnosis of patients with early-onset multiorgan autoimmune diseases in which STAT3 GOF is suspected should be confirmed by genetic testing and functional analysis to consider the introduction of targeted therapies.
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Affiliation(s)
- Koji Saito
- Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Japan
- Department of Pediatrics, National Hospital Organization Kochi National Hospital, Kochi, Japan
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Minoru Fujimoto
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan
- Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Eiji Funajima
- Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Japan
| | - Satoshi Serada
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan
- Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Japan
| | - Tomoharu Ohkawara
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan
- Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Masayuki Ishihara
- Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Mamiko Yamada
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Hisato Suzuki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Fuyuki Miya
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Mikiya Fujieda
- Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Tetsuji Naka
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan
- Division of Allergy and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba, Japan
- Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Japan
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2
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Qin H, Zhou L, Haque FT, Martin-Jimenez C, Trang A, Benveniste EN, Wang Q. Diverse signaling mechanisms and heterogeneity of astrocyte reactivity in Alzheimer's disease. J Neurochem 2024; 168:3536-3557. [PMID: 37932959 PMCID: PMC11839148 DOI: 10.1111/jnc.16002] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 11/08/2023]
Abstract
Alzheimer's disease (AD) affects various brain cell types, including astrocytes, which are the most abundant cell types in the central nervous system (CNS). Astrocytes not only provide homeostatic support to neurons but also actively regulate synaptic signaling and functions and become reactive in response to CNS insults through diverse signaling pathways including the JAK/STAT, NF-κB, and GPCR-elicited pathways. The advent of new technology for transcriptomic profiling at the single-cell level has led to increasing recognition of the highly versatile nature of reactive astrocytes and the context-dependent specificity of astrocyte reactivity. In AD, reactive astrocytes have long been observed in senile plaques and have recently been suggested to play a role in AD pathogenesis and progression. However, the precise contributions of reactive astrocytes to AD remain elusive, and targeting this complex cell population for AD treatment poses significant challenges. In this review, we summarize the current understanding of astrocyte reactivity and its role in AD, with a particular focus on the signaling pathways that promote astrocyte reactivity and the heterogeneity of reactive astrocytes. Furthermore, we explore potential implications for the development of therapeutics for AD. Our objective is to shed light on the complex involvement of astrocytes in AD and offer insights into potential therapeutic targets and strategies for treating and managing this devastating neurodegenerative disorder.
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Affiliation(s)
- Hongwei Qin
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA 35294
| | - Lianna Zhou
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA 35294
| | - Faris T. Haque
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA 35294
| | - Cynthia Martin-Jimenez
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA 30912
| | - Amy Trang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA 30912
| | - Etty N. Benveniste
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA 35294
| | - Qin Wang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA 30912
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3
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Bidgood GM, Keating N, Doggett K, Nicholson SE. SOCS1 is a critical checkpoint in immune homeostasis, inflammation and tumor immunity. Front Immunol 2024; 15:1419951. [PMID: 38947335 PMCID: PMC11211259 DOI: 10.3389/fimmu.2024.1419951] [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: 04/19/2024] [Accepted: 05/28/2024] [Indexed: 07/02/2024] Open
Abstract
The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental SOCS1 variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.
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Affiliation(s)
- Grace M. Bidgood
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Narelle Keating
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Karen Doggett
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Sandra E. Nicholson
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
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4
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Linossi EM, Li K, Veggiani G, Tan C, Dehkhoda F, Hockings C, Calleja DJ, Keating N, Feltham R, Brooks AJ, Li SS, Sidhu SS, Babon JJ, Kershaw NJ, Nicholson SE. Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands. Nat Commun 2021; 12:7032. [PMID: 34857742 PMCID: PMC8640019 DOI: 10.1038/s41467-021-26983-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 10/28/2021] [Indexed: 11/09/2022] Open
Abstract
Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and is an important module that facilitates recognition of targets bearing phosphorylated tyrosine (pTyr) residues. Here we identify an exosite on the SOCS2-SH2 domain which, when bound to a non-phosphorylated peptide (F3), enhances SH2 affinity for canonical phosphorylated ligands. Solution of the SOCS2/F3 crystal structure reveals F3 as an α-helix which binds on the opposite side of the SH2 domain to the phosphopeptide binding site. F3:exosite binding appears to stabilise the SOCS2-SH2 domain, resulting in slower dissociation of phosphorylated ligands and consequently, enhances binding affinity. This biophysical enhancement of SH2:pTyr binding affinity translates to increase SOCS2 inhibition of GH signaling.
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Affiliation(s)
- Edmond M Linossi
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Kunlun Li
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Gianluca Veggiani
- The Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Cyrus Tan
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Farhad Dehkhoda
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Colin Hockings
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Dale J Calleja
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Narelle Keating
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Rebecca Feltham
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Andrew J Brooks
- The University of Queensland Diamantina Institute, Woolloongabba, QLD, 4102, Australia
| | - Shawn S Li
- Department of Biochemistry and the Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada
| | - Sachdev S Sidhu
- The Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
| | - Jeffrey J Babon
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Nadia J Kershaw
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
| | - Sandra E Nicholson
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
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5
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Nara H, Watanabe R. Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism. Int J Mol Sci 2021; 22:ijms22189889. [PMID: 34576053 PMCID: PMC8471880 DOI: 10.3390/ijms22189889] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/11/2022] Open
Abstract
Interleukin (IL)-6 has been studied since its discovery for its role in health and diseases. It is one of the most important pro-inflammatory cytokines. IL-6 was reported as an exacerbating factor in coronavirus disease. In recent years, it has become clear that the function of muscle-derived IL-6 is different from what has been reported so far. Exercise is accompanied by skeletal muscle contraction, during which, several bioactive substances, collectively named myokines, are secreted from the muscles. Many reports have shown that IL-6 is the most abundant myokine. Interestingly, it was indicated that IL-6 plays opposing roles as a myokine and as a pro-inflammatory cytokine. In this review, we discuss why IL-6 has different functions, the signaling mode of hyper-IL-6 via soluble IL-6 receptor (sIL-6R), and the involvement of soluble glycoprotein 130 in the suppressive effect of hyper-IL-6. Furthermore, the involvement of a disintegrin and metalloprotease family molecules in the secretion of sIL-6R is described. One of the functions of muscle-derived IL-6 is lipid metabolism in the liver. However, the differences between the functions of IL-6 as a pro-inflammatory cytokine and the functions of muscle-derived IL-6 are unclear. Although the involvement of myokines in lipid metabolism in adipocytes was previously discussed, little is known about the direct relationship between nonalcoholic fatty liver disease and muscle-derived IL-6. This review is the first to discuss the relationship between the function of IL-6 in diseases and the function of muscle-derived IL-6, focusing on IL-6 signaling and lipid metabolism in the liver.
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6
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Villar-Fincheira P, Sanhueza-Olivares F, Norambuena-Soto I, Cancino-Arenas N, Hernandez-Vargas F, Troncoso R, Gabrielli L, Chiong M. Role of Interleukin-6 in Vascular Health and Disease. Front Mol Biosci 2021; 8:641734. [PMID: 33786327 PMCID: PMC8004548 DOI: 10.3389/fmolb.2021.641734] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/01/2021] [Indexed: 01/08/2023] Open
Abstract
IL-6 is usually described as a pleiotropic cytokine produced in response to tissue injury or infection. As a pro-inflammatory cytokine, IL-6 activates innate and adaptative immune responses. IL-6 is released in the innate immune response by leukocytes as well as stromal cells upon pattern recognition receptor activation. IL-6 then recruits immune cells and triggers B and T cell response. Dysregulated IL-6 activity is associated with pathologies involving chronic inflammation and autoimmunity, including atherosclerosis. However, IL-6 is also produced and released under beneficial conditions, such as exercise, where IL-6 is associated with the anti-inflammatory and metabolic effects coupled with physical adaptation to intense training. Exercise-associated IL-6 acts on adipose tissue to induce lipogenesis and on arteries to induce adaptative vascular remodeling. These divergent actions could be explained by complex signaling networks. Classical IL-6 signaling involves a membrane-bound IL-6 receptor and glycoprotein 130 (gp130), while trans-signaling relies on a soluble version of IL-6R (sIL-6R) and membrane-bound gp130. Trans-signaling, but not the classical pathway, is regulated by soluble gp130. In this review, we discuss the similarities and differences in IL-6 cytokine and myokine signaling to explain the differential and opposite effects of this protein during inflammation and exercise, with a special focus on the vascular system.
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Affiliation(s)
- Paulina Villar-Fincheira
- Advanced Center for Chronic Diseases & CEMC, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
| | - Fernanda Sanhueza-Olivares
- Advanced Center for Chronic Diseases & CEMC, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
| | - Ignacio Norambuena-Soto
- Advanced Center for Chronic Diseases & CEMC, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
| | - Nicole Cancino-Arenas
- Advanced Center for Chronic Diseases & CEMC, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
| | - Felipe Hernandez-Vargas
- Advanced Center for Chronic Diseases & CEMC, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
| | - Rodrigo Troncoso
- Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile, Santiago, Chile
| | - Luigi Gabrielli
- Advanced Center for Chronic Diseases, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- *Correspondence: Luigi Gabrielli, ; Mario Chiong,
| | - Mario Chiong
- Advanced Center for Chronic Diseases & CEMC, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
- *Correspondence: Luigi Gabrielli, ; Mario Chiong,
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7
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Ding J, Xu K, Sun S, Qian C, Yin S, Xie H, Zhou L, Zheng S, Zhang W. SOCS1 blocks G1-S transition in hepatocellular carcinoma by reducing the stability of the CyclinD1/CDK4 complex in the nucleus. Aging (Albany NY) 2020; 12:3962-3975. [PMID: 32096766 PMCID: PMC7066915 DOI: 10.18632/aging.102865] [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: 10/01/2019] [Accepted: 02/04/2020] [Indexed: 12/24/2022]
Abstract
Inhibitors of the CDK family of proteins have been approved for the treatment of a variety of tumours; however, the development of new drugs administered in combination with CDK inhibitors is expected to improve the therapeutic effect. We identified the function of suppressor of cytokine signalling 1 (SOCS1) in hepatocellular carcinoma (HCC) cell models and the xenograft mouse model. When SOCS1 expression was artificially upregulated, HCC cell lines were arrested at the G1-S transition in the cell cycle. Interestingly, during this process, total CyclinD1 protein increased, but the effective proportion decreased. We found that the deficiency of CyclinD1 in the nucleus is probably due to the decrease in the stability of nuclear CyclinD1 caused by the ubiquitin-based degradation of P21, thus inhibiting the progression of the cell cycle to S phase. After P21 expression was increased, the levels of the component that inactivates CyclinD1 decreased as expected. It showed that P21 has a partial promoting effect on cancer. SOCS1 is a good indicator of prognosis, tumour size and long-term survival after resection. SOCS1 is expected to become a drug target in combined with CDK family inhibitors.
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Affiliation(s)
- Jun Ding
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
| | - Kangdi Xu
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.,Ningbo Medical Center LIHUILI Hospital, Ningbo, Zhejiang Province, China
| | - Suwan Sun
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, China.,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.,National Clinical Research Center for Infectious Diseases, Hangzhou, Zhejiang Province, China
| | - Chao Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
| | - Shengyong Yin
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
| | - Haiyang Xie
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
| | - Lin Zhou
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, China
| | - Wei Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China.,Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
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8
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Saint-Germain E, Mignacca L, Huot G, Acevedo M, Moineau-Vallée K, Calabrese V, Bourdeau V, Rowell MC, Ilangumaran S, Lessard F, Ferbeyre G. Phosphorylation of SOCS1 Inhibits the SOCS1–p53 Tumor Suppressor Axis. Cancer Res 2019; 79:3306-3319. [DOI: 10.1158/0008-5472.can-18-1503] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 03/21/2019] [Accepted: 05/13/2019] [Indexed: 11/16/2022]
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9
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Wang X, Mulas F, Yi W, Brunn A, Nishanth G, Just S, Waisman A, Brück W, Deckert M, Schlüter D. OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes. EMBO J 2019; 38:embj.2018100947. [PMID: 30944096 DOI: 10.15252/embj.2018100947] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 02/20/2019] [Accepted: 02/28/2019] [Indexed: 01/31/2023] Open
Abstract
Astrocytes are critical regulators of neuroinflammation in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Growing evidence indicates that ubiquitination of signaling molecules is an important cell-intrinsic mechanism governing astrocyte function during MS and EAE Here, we identified an upregulation of the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in astrocytes during MS and EAE Mice with astrocyte-specific OTUB1 ablation developed more severe EAE due to increased leukocyte accumulation, proinflammatory gene transcription, and demyelination in the spinal cord as compared to control mice. OTUB1-deficient astrocytes were hyperactivated in response to IFN-γ, a fingerprint cytokine of encephalitogenic T cells, and produced more proinflammatory cytokines and chemokines than control astrocytes. Mechanistically, OTUB1 inhibited IFN-γ-induced Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling by K48 deubiquitination and stabilization of the JAK2 inhibitor suppressor of cytokine signaling 1 (SOCS1). Thus, astrocyte-specific OTUB1 is a critical inhibitor of neuroinflammation in CNS autoimmunity.
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Affiliation(s)
- Xu Wang
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany .,Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Floriana Mulas
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.,Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Wenjing Yi
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.,Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Anna Brunn
- Department of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Gopala Nishanth
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.,Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Sissy Just
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.,Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Wolfgang Brück
- Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Martina Deckert
- Department of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Dirk Schlüter
- Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany .,Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.,Organ-specific Immune Regulation, Helmholtz-Center for Infection Research, Braunschweig, Germany
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10
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SOCS1 and its Potential Clinical Role in Tumor. Pathol Oncol Res 2019; 25:1295-1301. [DOI: 10.1007/s12253-019-00612-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 02/04/2019] [Indexed: 10/27/2022]
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11
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The Two-Faced Cytokine IL-6 in Host Defense and Diseases. Int J Mol Sci 2018; 19:ijms19113528. [PMID: 30423923 PMCID: PMC6274717 DOI: 10.3390/ijms19113528] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 10/30/2018] [Accepted: 11/06/2018] [Indexed: 02/07/2023] Open
Abstract
Interleukein-6 (IL-6), is produced locally from infectious or injured lesions and is delivered to the whole body via the blood stream, promptly activating the host defense system to perform diverse functions. However, excessive or sustained production of IL-6 is involved in various diseases. In diseases, the IL-6 inhibitory strategy begins with the development of the anti-IL-6 receptor antibody, tocilizumab (TCZ). This antibody has shown remarkable effects on Castleman disease, rheumatoid arthritis and juvenile idiopathic arthritis. In 2017, TCZ was proven to work effectively against giant cell arteritis, Takayasu arteritis and cytokine releasing syndrome, initiating a new era for the treatment of these diseases. In this study, the defensive functions of IL-6 and various pathological conditions are compared. Further, the diseases of which TCZ has been approved for treatment are summarized, the updated results of increasing off-label use of TCZ for various diseases are reviewed and the conditions for which IL-6 inhibition might have a beneficial role are discussed. Given the involvement of IL-6 in many pathologies, the diseases that can be improved by IL-6 inhibition will expand. However, the important role of IL-6 in host defense should always be kept in mind in clinical practice.
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Abstract
Conventional root canal therapies yield high success rates. The treatment outcomes are negatively affected by the presence of apical periodontitis (AP), which reflects active root canal infection and inflammatory responses. Also, cross-sectional studies revealed surprisingly high prevalence of AP in the general population, especially in those with prior endodontic treatments. Hence, AP is an ongoing disease entity in endodontics that needs further understanding of the pathogenesis and disease progression. The current Chapter will discuss the basic mechanisms of AP with emphasis on emerging role of epigenetic regulators in regulation of inflammatory mediators.
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Abstract
The development and activity of our immune system are largely controlled by the action of pleiotropic cytokines and growth factors, small secreted proteins, which bind to receptors on the surface of immune cells to initiate an appropriate physiological response. Cytokine signalling is predominantly executed by intracellular proteins known as the Janus kinases (JAKs) and the signal transducers and activators of transcriptions (STATs). Although the 'nuts and bolts' of cytokine-activated pathways have been well established, the nuanced way in which distinct cellular outcomes are achieved and the precise molecular details of the proteins that regulate these pathways are still being elucidated. This is highlighted by the intricate role of the suppressor of cytokine signalling (SOCS) proteins. The SOCS proteins act as negative feedback inhibitors, dampening specific cytokine signals to prevent excessive cellular responses and returning the cell to a homeostatic state. A great deal of study has demonstrated their ability to inhibit these pathways at the receptor complex, either through direct inhibition of JAK activity or by targeting the receptor complex for proteasomal degradation. Detailed analysis of individual SOCS proteins is slowly revealing the complex and highly controlled manner by which they can achieve specificity for distinct substrates. However, for many of the SOCS, a level of detail is still lacking, including confident identification of the full suite of tyrosine phosphorylated targets of their SH2 domain. This review will highlight the general mechanisms which govern SOCS specificity of action and discuss the similarities and differences between selected SOCS proteins, focusing on CIS, SOCS1 and SOCS3. Because of the functional and sequence similarities within the SOCS family, we will also discuss the evidence for functional redundancy.
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Affiliation(s)
- Edmond M Linossi
- a Walter and Eliza Hall Institute of Medical Research , Parkville , Australia
- b Department of Medical Biology , University of Melbourne , Parkville , Australia
| | - Dale J Calleja
- a Walter and Eliza Hall Institute of Medical Research , Parkville , Australia
| | - Sandra E Nicholson
- a Walter and Eliza Hall Institute of Medical Research , Parkville , Australia
- b Department of Medical Biology , University of Melbourne , Parkville , Australia
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14
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Giotis ES, Ross CS, Robey RC, Nohturfft A, Goodbourn S, Skinner MA. Constitutively elevated levels of SOCS1 suppress innate responses in DF-1 immortalised chicken fibroblast cells. Sci Rep 2017; 7:17485. [PMID: 29235573 PMCID: PMC5727488 DOI: 10.1038/s41598-017-17730-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 11/29/2017] [Indexed: 01/08/2023] Open
Abstract
The spontaneously immortalised DF-1 cell line is rapidly replacing its progenitor primary chicken embryo fibroblasts (CEFs) for studies on avian viruses such as avian influenza but no comprehensive study has as yet been reported comparing their innate immunity phenotypes. We conducted microarray analyses of DF-1 and CEFs, under both normal and stimulated conditions using chicken interferon-α (chIFN-α) and the attenuated infectious bursal disease virus vaccine strain PBG98. We found that DF-1 have an attenuated innate response compared to CEFs. Basal expression levels of Suppressor of Cytokine Signalling 1 (chSOCS1), a negative regulator of cytokine signalling in mammals, are 16-fold higher in DF-1 than in CEFs. The chSOCS1 “SOCS box” domain (which in mammals, interacts with an E3 ubiquitin ligase complex) is not essential for the inhibition of cytokine-induced JAK/STAT signalling activation in DF-1. Overexpression of SOCS1 in chIFN-α-stimulated DF-1 led to a relative decrease in expression of interferon-stimulated genes (ISGs; MX1 and IFIT5) and increased viral yield in response to PBG98 infection. Conversely, knockdown of SOCS1 enhanced induction of ISGs and reduced viral yield in chIFN-α-stimulated DF-1. Consequently, SOCS1 reduces induction of the IFN signalling pathway in chicken cells and can potentiate virus replication.
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Affiliation(s)
- E S Giotis
- Section of Virology, School of Medicine, St Mary's Campus, Imperial College London, London, W2 1PG, UK
| | - C S Ross
- Institute for Infection and Immunity, St George's, University of London, London, SW17 0RE, UK
| | - R C Robey
- Section of Virology, School of Medicine, St Mary's Campus, Imperial College London, London, W2 1PG, UK
| | - A Nohturfft
- Institute for Infection and Immunity, St George's, University of London, London, SW17 0RE, UK
| | - S Goodbourn
- Institute for Infection and Immunity, St George's, University of London, London, SW17 0RE, UK
| | - M A Skinner
- Section of Virology, School of Medicine, St Mary's Campus, Imperial College London, London, W2 1PG, UK.
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15
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Sugase T, Takahashi T, Serada S, Fujimoto M, Hiramatsu K, Ohkawara T, Tanaka K, Miyazaki Y, Makino T, Kurokawa Y, Yamasaki M, Nakajima K, Kishimoto T, Mori M, Doki Y, Naka T. SOCS1 Gene Therapy Improves Radiosensitivity and Enhances Irradiation-Induced DNA Damage in Esophageal Squamous Cell Carcinoma. Cancer Res 2017; 77:6975-6986. [DOI: 10.1158/0008-5472.can-17-1525] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 09/05/2017] [Accepted: 10/11/2017] [Indexed: 11/16/2022]
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16
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Maruoka M, Kedashiro S, Ueda Y, Mizutani K, Takai Y. Nectin-4 co-stimulates the prolactin receptor by interacting with SOCS1 and inhibiting its activity on the JAK2-STAT5a signaling pathway. J Biol Chem 2017; 292:6895-6909. [PMID: 28258213 PMCID: PMC5409460 DOI: 10.1074/jbc.m116.769091] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 03/02/2017] [Indexed: 01/02/2023] Open
Abstract
Cell-surface cytokine receptors are regulated by their cis-interacting stimulatory and inhibitory co-receptors. We previously showed that the Ig-like cell-adhesion molecule nectin-4 cis-interacts with the prolactin receptor through the extracellular region and stimulates prolactin-induced prolactin receptor activation and signaling, resulting in alveolar development in the mouse mammary gland. However, it remains unknown how this interaction stimulates these effects. We show here that the cis-interaction of the extracellular region of nectin-4 with the prolactin receptor was not sufficient for eliciting these effects and that the cytoplasmic region of nectin-4 was also required for this interaction. The cytoplasmic region of nectin-4 directly interacted with suppressor of cytokine signaling 1 (SOCS1), but not SOCS3, JAK2, or STAT5a, and inhibited the interaction of SOCS1 with JAK2, eventually resulting in the increased phosphorylation of STAT5a. The juxtamembrane region of nectin-4 interacted with the Src homology 2 domain of SOCS1. Both the interaction of nectin-4 with the extracellular region of the prolactin receptor and the interaction of SOCS1 with the cytoplasmic region of nectin-4 were required for the stimulatory effect of nectin-4 on the prolactin-induced prolactin receptor activation. The third Ig-like domain of nectin-4 and the second fibronectin type III domain of the prolactin receptor were involved in this cis-interaction, and both the extracellular and transmembrane regions of nectin-4 and the prolactin receptor were required for this direct interaction. These results indicate that nectin-4 serves as a stimulatory co-receptor for the prolactin receptor by regulating the feedback inhibition of SOCS1 in the JAK2-STAT5a signaling pathway.
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Affiliation(s)
- Masahiro Maruoka
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047
- the Health Metrics Development Team, RIKEN Compass to Healthy Life Research Complex Program, 6-7-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, and
| | - Shin Kedashiro
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047
| | - Yuki Ueda
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047
| | - Kiyohito Mizutani
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047,
| | - Yoshimi Takai
- From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047,
- the Pathophysiological and Health Science Team, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
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17
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Sugase T, Takahashi T, Serada S, Nakatsuka R, Fujimoto M, Ohkawara T, Hara H, Nishigaki T, Tanaka K, Miyazaki Y, Makino T, Kurokawa Y, Yamasaki M, Nakajima K, Takiguchi S, Kishimoto T, Mori M, Doki Y, Naka T. Suppressor of cytokine signaling-1 gene therapy induces potent antitumor effect in patient-derived esophageal squamous cell carcinoma xenograft mice. Int J Cancer 2017; 140:2608-2621. [PMID: 28233302 DOI: 10.1002/ijc.30666] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 01/07/2017] [Accepted: 02/07/2017] [Indexed: 12/21/2022]
Abstract
Chronic inflammation is involved in cancer growth in esophageal squamous cell carcinoma (ESCC), which is a highly refractory cancer with poor prognosis. This study investigated the antitumor effect and mechanisms of SOCS1 gene therapy for ESCC. Patients with ESCC showed epigenetics silencing of SOCS1 gene by methylation in the CpG islands. We infected 10 ESCC cells with an adenovirus-expressing SOCS1 (AdSOCS1) to examine the antitumor effect and mechanism of SOCS1 overexpression. SOCS1 overexpression markedly decreased the proliferation of all ESCC cell lines and induced apoptosis. Also, SOCS1 inhibited the proliferation of ESCC cells via multiple signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and focal adhesion kinase (FAK)/p44/42 mitogen-activated protein kinase (p44/42 MAPK). Additionally, we established two xenograft mouse models in which TE14 ESCC cells or ESCC patient-derived tissues (PDX) were subcutaneously implanted. Mice were intra-tumorally injected with AdSOCS1 or control adenovirus vector (AdLacZ). In mice, tumor volumes and tumor weights were significantly lower in mice treated with AdSOCS1 than that with AdLacZ as similar mechanism to the in vitro findings. The Ki-67 index of tumors treated with AdSOCS1 was significantly lower than that with AdLacZ, and SOCS1 gene therapy induced apoptosis. These findings demonstrated that overexpression of SOCS1 has a potent antitumor effect against ESCC both in vitro and in vivo including PDX mice. SOCS1 gene therapy may be a promising approach for the treatment of ESCC.
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Affiliation(s)
- Takahito Sugase
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.,Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.,Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
| | - Satoshi Serada
- Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
| | - Rie Nakatsuka
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.,Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
| | - Minoru Fujimoto
- Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
| | - Tomoharu Ohkawara
- Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
| | - Hisashi Hara
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.,Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
| | - Takahiko Nishigaki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.,Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
| | - Koji Tanaka
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yasuhiro Miyazaki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Makoto Yamasaki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tadamitsu Kishimoto
- Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuji Naka
- Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan
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18
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Narazaki M, Tanaka T, Kishimoto T. The role and therapeutic targeting of IL-6 in rheumatoid arthritis. Expert Rev Clin Immunol 2017; 13:535-551. [PMID: 28494214 DOI: 10.1080/1744666x.2017.1295850] [Citation(s) in RCA: 163] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is an autoimmune chronic disease with joint and systemic inflammation and it has been found that interleukin-6 (IL-6) plays a key role in RA. Indeed, various clinical studies have proved that the first-in-class IL-6 inhibitor, tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, showed outstanding efficacy in RA. Areas covered: We review here the role of IL-6 in the inflammatory conditions and how IL-6 contributes to pathogenesis of RA, what induces IL-6 and how IL-6 expression is regulated. Furthermore, clinical studies of tocilizumab for RA are summarized, Expert commentary: We review and discuss the prospects for future applications of IL-6 targeting therapy and new therapeutic strategies targeting IL-6. Finally, we discuss relevant issues with regard to the clinical management of IL-6 blockade in RA.
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Affiliation(s)
- Masashi Narazaki
- a Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine , Osaka University , Osaka , Japan.,b Department of Immunopathology, World Premier International Immunology Frontier Research Center , Osaka University , Osaka , Japan
| | - Toshio Tanaka
- b Department of Immunopathology, World Premier International Immunology Frontier Research Center , Osaka University , Osaka , Japan.,c Department of Clinical Application of Biologics, Osaka University Graduate School of Medicine , Osaka University , Osaka , Japan
| | - Tadamitsu Kishimoto
- d Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center , Osaka University , Osaka , Japan
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19
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Jiang M, Zhang WW, Liu P, Yu W, Liu T, Yu J. Dysregulation of SOCS-Mediated Negative Feedback of Cytokine Signaling in Carcinogenesis and Its Significance in Cancer Treatment. Front Immunol 2017; 8:70. [PMID: 28228755 PMCID: PMC5296614 DOI: 10.3389/fimmu.2017.00070] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 01/16/2017] [Indexed: 01/30/2023] Open
Abstract
Suppressor of cytokine signaling (SOCS) proteins are major negative feedback regulators of cytokine signaling mediated by the Janus kinase (JAK)-signal transducer and activator of transcription signaling pathway. In particular, SOCS1 and SOCS3 are strong inhibitors of JAKs and can play pivotal roles in the development and progression of cancers. The abnormal expression of SOCS1 and SOCS3 in cancer cells is associated with the dysregulation of cell growth, migration, and death induced by multiple cytokines and hormones in human carcinomas. In addition, the mechanisms involved in SOCS1- and SOCS3-regulated abnormal development and activation of immune cells in carcinogenesis, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells, are still unclear. Therefore, this study aims to further discuss the molecules and signal pathways regulating the expression and function of SOCS1 and SOCS3 in various types of cancers and elucidate the feasibility and efficiency of SOCS-based target therapeutic strategy in anticancer treatment.
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Affiliation(s)
- Mengmeng Jiang
- Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Wen-Wen Zhang
- Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Pengpeng Liu
- Cancer Molecular Diagnostic Center, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital , Tianjin , China
| | - Wenwen Yu
- Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Ting Liu
- Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jinpu Yu
- Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Cancer Molecular Diagnostic Center, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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20
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Sun JJ, Lan JF, Xu JD, Niu GJ, Wang JX. Suppressor of cytokine signaling 2 (SOCS2) negatively regulates the expression of antimicrobial peptides by affecting the Stat transcriptional activity in shrimp Marsupenaeus japonicus. FISH & SHELLFISH IMMUNOLOGY 2016; 56:473-482. [PMID: 27492125 DOI: 10.1016/j.fsi.2016.07.037] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 07/13/2016] [Accepted: 07/31/2016] [Indexed: 06/06/2023]
Abstract
The suppressor of cytokine signaling (SOCS) family is a kind of negative regulators in the Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway in mammals and Drosophila. In kuruma shrimp, Marsupenaeus japonicus, SOCS2 is identified and its expression can be stimulated by peptidoglycan and polycytidylic acid. However, if SOCS2 participates in regulating Jak/Stat pathway in shrimp still needs further study. In this study, SOCS2 with Src homology 2 domain and SOCS box was identified in kuruma shrimp, M. japonicus. SOCS2 existed in hemocytes, heart, hepatopancreas, gills, stomach, and intestine, the expression of SOCS2 was upregulated significantly in the hemocytes and intestine of shrimp challenged with Vibrio anguillarum at 6 h. To analyze SOCS2 function in shrimp immunity, bacterial clearance and survival rate were analyzed after knockdown of SOCS2 in shrimp challenged with V. anguillarum. Results showed that bacterial clearance increased, and the survival rate improved significantly comparing with controls. The SOCS2 was expressed in Escherichia coli and the recombinant SOCS2 was injected into shrimp, and Stat phosphorylation and translocation were analyzed. The result showed that "overexpression" of SOCS2 declined Stat phosphorylation level and inhibited Stat translocation into the nucleus. After knockdown of SOCS2 in shrimp prior to V. anguillarum infection, the expression level of antimicrobial peptides, including anti-lipopolysaccharide factors C1, C2 and D1, and Crustin I was upregulated significantly, and the expression of the AMPs was declined after recombinant SOCS2 injection. The SOCS2 expression was also decreased in Stat-knockdown shrimp challenged by V. anguillarum at 6 and 12 h. Therefore, SOCS2 negatively regulates the AMP expression by inhibiting Stat phosphorylation and translocation into nucleus in shrimp, meanwhile, SOCS2 expression was also regulated by Jak/Stat pathway.
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Affiliation(s)
- Jie-Jie Sun
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China
| | - Jiang-Feng Lan
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China.
| | - Ji-Dong Xu
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China
| | - Guo-Juan Niu
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China
| | - Jin-Xing Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan, Shandong 250100, China.
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21
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Leitner NR, Witalisz-Siepracka A, Strobl B, Müller M. Tyrosine kinase 2 - Surveillant of tumours and bona fide oncogene. Cytokine 2015; 89:209-218. [PMID: 26631911 DOI: 10.1016/j.cyto.2015.10.015] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 10/29/2015] [Indexed: 12/16/2022]
Abstract
Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which transduces cytokine and growth factor signalling. Analysis of TYK2 loss-of-function revealed its important role in immunity to infection, (auto-) immunity and (auto-) inflammation. TYK2-deficient patients unravelled high similarity between mice and men with respect to cellular signalling functions and basic immunology. Genome-wide association studies link TYK2 to several autoimmune and inflammatory diseases as well as carcinogenesis. Due to its cytokine signalling functions TYK2 was found to be essential in tumour surveillance. Lately TYK2 activating mutants and fusion proteins were detected in patients diagnosed with leukaemic diseases suggesting that TYK2 is a potent oncogene. Here we review the cell intrinsic and extrinsic functions of TYK2 in the characteristics preventing and enabling carcinogenesis. In addition we describe an unexpected function of kinase-inactive TYK2 in tumour rejection.
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Affiliation(s)
- Nicole R Leitner
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Agnieszka Witalisz-Siepracka
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Birgit Strobl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria
| | - Mathias Müller
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
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22
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Tagami-Nagata N, Serada S, Fujimoto M, Tanemura A, Nakatsuka R, Ohkawara T, Murota H, Kishimoto T, Katayama I, Naka T. Suppressor of cytokine signalling-1 induces significant preclinical antitumor effect in malignant melanoma cells. Exp Dermatol 2015; 24:864-71. [PMID: 26173926 DOI: 10.1111/exd.12802] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2015] [Indexed: 02/01/2023]
Abstract
Malignant melanoma is the most aggressive form of skin cancer, responsible for the majority of skin cancer-related deaths. Metastatic melanoma is resistant to surgery, radiation or chemotherapy, and an effective therapy has not yet been established. Our study investigated the therapeutic potential of the suppressor of cytokine signalling-1 (SOCS-1), an endogenous inhibitor of the intracellular cytokine signalling pathway, for treating melanoma. Adenovirus vectors encoding the SOCS-1 gene were used to overexpress SOCS-1 in three melanoma cell lines (G361, SK-MEL5 and SK-MEL28). In G361 and SK-MEL5, overexpression of SOCS-1 significantly reduced cell proliferation and induced apoptosis in vitro and in vivo. Furthermore, we indicated that the antiproliferative effect of SOCS-1 correlated not only with decreased levels of the activation of signal transducer and activator of transcription (STAT)3 but also with increased levels of p53 expression and phosphorylation. These findings indicate the potential for clinical use of SOCS-1 for melanoma treatment.
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Affiliation(s)
- Naoko Tagami-Nagata
- Laboratory of Immune Signal, National Institute of Biomedical Innovation, Ibaraki, Japan.,Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Satoshi Serada
- Laboratory of Immune Signal, National Institute of Biomedical Innovation, Ibaraki, Japan
| | - Minoru Fujimoto
- Laboratory of Immune Signal, National Institute of Biomedical Innovation, Ibaraki, Japan
| | - Atsushi Tanemura
- Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Rie Nakatsuka
- Laboratory of Immune Signal, National Institute of Biomedical Innovation, Ibaraki, Japan.,Department of Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomoharu Ohkawara
- Laboratory of Immune Signal, National Institute of Biomedical Innovation, Ibaraki, Japan
| | - Hiroyuki Murota
- Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tadamitsu Kishimoto
- Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Ichiro Katayama
- Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuji Naka
- Laboratory of Immune Signal, National Institute of Biomedical Innovation, Ibaraki, Japan
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Monk JM, Liddle DM, De Boer AA, Brown MJ, Power KA, Ma DW, Robinson LE. Fish-oil-derived n-3 PUFAs reduce inflammatory and chemotactic adipokine-mediated cross-talk between co-cultured murine splenic CD8+ T cells and adipocytes. J Nutr 2015; 145:829-38. [PMID: 25833786 DOI: 10.3945/jn.114.205443] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 12/30/2014] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Obese adipose tissue (AT) inflammation is characterized by dysregulated adipokine production and immune cell accumulation. Cluster of differentiation (CD) 8+ T cell AT infiltration represents a critical step that precedes macrophage infiltration. n-3 (ω-3) Polyunsaturated fatty acids (PUFAs) exert anti-inflammatory effects in obese AT, thereby disrupting AT inflammatory paracrine signaling. OBJECTIVE We assessed the effect of n-3 PUFAs on paracrine interactions between adipocytes and primary CD8+ T cells co-cultured at the cellular ratio observed in obese AT. METHODS C57BL/6 mice were fed either a 3% menhaden fish-oil + 7% safflower oil (FO) diet (wt:wt) or an isocaloric 10% safflower oil (wt:wt) control (CON) for 3 wk, and splenic CD8+ T cells were isolated by positive selection (via magnetic microbeads) and co-cultured with 3T3-L1 adipocytes. Co-cultures were unstimulated (cells alone), T cell receptor stimulated, or lipopolysaccharide (LPS) stimulated for 24 h. RESULTS In LPS-stimulated co-cultures, FO reduced secreted protein concentrations of interleukin (IL)-6 (-42.6%), tumor necrosis factor α (-67%), macrophage inflammatory protein (MIP) 1α (-52%), MIP-1β (-62%), monocyte chemotactic protein (MCP) 1 (-23%), and MCP-3 (-19%) vs. CON, which coincided with a 74% reduction in macrophage chemotaxis toward secreted chemotaxins in LPS-stimulated FO-enriched co-culture-conditioned media. FO increased mRNA expression of the inflammatory signaling negative regulators monocyte chemoattractant 1-induced protein (Mcpip; +9.3-fold) and suppressor of cytokine signaling 3 (Socs3; +1.7-fold), whereas FO reduced activation of inflammatory transcription factors nuclear transcription factor κB (NF-κB) p65 and signal transducer and activator of transcription 3 (STAT3) by 27% and 33%, respectively. Finally, mRNA expression of the inflammasome components Caspase1 (-36.4%), Nod-like receptor family pyrin domain containing 3 (Nlrp3; -99%), and Il1b (-68.8%) were decreased by FO compared with CON (P ≤ 0.05). CONCLUSION FO exerted an anti-inflammatory and antichemotactic effect on the cross-talk between CD8+ T cells and adipocytes and has implications in mitigating macrophage-centered AT-driven components of the obese phenotype.
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Affiliation(s)
- Jennifer M Monk
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada; and Guelph Food Research Centre, Agriculture Agri-Food Canada, Guelph, Canada
| | - Danyelle M Liddle
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada; and
| | - Anna A De Boer
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada; and
| | - Morgan J Brown
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada; and
| | - Krista A Power
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada; and Guelph Food Research Centre, Agriculture Agri-Food Canada, Guelph, Canada
| | - David Wl Ma
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada; and
| | - Lindsay E Robinson
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada; and
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The role of suppressors of cytokine signalling in human neoplasms. Mol Biol Int 2014; 2014:630797. [PMID: 24757565 PMCID: PMC3976820 DOI: 10.1155/2014/630797] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 02/02/2014] [Accepted: 02/04/2014] [Indexed: 12/28/2022] Open
Abstract
Suppressors of cytokine signalling 1-7 (SOCS1-7) and cytokine-inducible SH2-containing protein (CIS) are a group of intracellular proteins that are well known as JAK-STAT and several other signalling pathways negative feedback regulators. More recently several members have been identified as tumour suppressors and dysregulation of their biological roles in controlling cytokine and growth factor signalling may contribute to the development of many solid organ and haematological malignancies. This review explores their biological functions and their possible tumour suppressing role in human neoplasms.
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De Boer AA, Monk JM, Robinson LE. Docosahexaenoic acid decreases pro-inflammatory mediators in an in vitro murine adipocyte macrophage co-culture model. PLoS One 2014; 9:e85037. [PMID: 24465472 PMCID: PMC3896343 DOI: 10.1371/journal.pone.0085037] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 11/24/2013] [Indexed: 01/28/2023] Open
Abstract
Paracrine interactions between adipocytes and macrophages contribute to chronic inflammation in obese adipose tissue. Dietary strategies to mitigate such inflammation include long-chain polyunsaturated fatty acids, docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, which act through PPARγ-dependent and independent pathways. We utilized an in vitro co-culture model designed to mimic the ratio of macrophages:adipocytes in obese adipose tissue, whereby murine 3T3-L1 adipocytes were cultured with RAW 264.7 macrophages in direct contact, or separated by a trans-well membrane (contact-independent mechanism), with 125 µM of albumin-complexed DHA, EPA, palmitic acid (PA), or albumin alone (control). Thus, we studied the effect of physical cell contact versus the presence of soluble factors, with or without a PPARγ antagonist (T0070907) in order to elucidate putative mechanisms. After 12 hr, DHA was the most anti-inflammatory, decreasing MCP1 and IL-6 secretion in the contact system (−57%, −63%, respectively, p≤0.05) with similar effects in the trans-well system. The trans-well system allowed for isolation of cell types for inflammatory mediator analysis. DHA decreased mRNA expression (p<0.05) of Mcp1 (−7.1 fold) and increased expression of the negative regulator, Mcp1-IP (+1.5 fold). In macrophages, DHA decreased mRNA expression of pro-inflammatory M1 polarization markers (p≤0.05), Nos2 (iNOS; −7 fold), Tnfα (−4.2 fold) and Nfκb (−2.3 fold), while increasing anti-inflammatory Tgfβ1 (+1.7 fold). Interestingly, the PPARγ antagonist co-administered with DHA or EPA in co-culture reduced (p≤0.05) adiponectin cellular protein, without modulating other cytokines (protein or mRNA). Overall, our findings suggest that DHA may lessen the degree of MCP1 and IL-6 secreted from adipocytes, and may reduce the degree of M1 polarization of macrophages recruited to adipose tissue, thereby decreasing the intensity of pro-inflammatory cross-talk between adipocytes and macrophages in obese adipose tissue.
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Affiliation(s)
- Anna A. De Boer
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada
| | - Jennifer M. Monk
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada
| | - Lindsay E. Robinson
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada
- * E-mail:
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Babon JJ, Varghese LN, Nicola NA. Inhibition of IL-6 family cytokines by SOCS3. Semin Immunol 2014; 26:13-9. [PMID: 24418198 DOI: 10.1016/j.smim.2013.12.004] [Citation(s) in RCA: 154] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 12/23/2013] [Indexed: 01/06/2023]
Abstract
IL-6 a multi-functional cytokine with important effects in both inflammation and haematopoiesis. SOCS3 is the primary inhibitor of IL-6 signalling, interacting with gp130, the common shared chain of the IL-6 family of cytokines, and JAK1, JAK2 and TYK2 to control both the duration of signalling and the biological response. Recent biochemical and structural studies have shown SOCS3 binds to only these three JAKs, all of which are associated with IL-6 signalling, and not JAK3. This specificity is determined by a three residue "GQM" motif in the kinase domain of JAK1, JAK2 and TYK2. SOCS3 binds to JAK and gp130 simultaneously, and inhibits JAK activity in an ATP-independent manner by partially occluding the kinase's substrate binding groove with its kinase inhibitory region. We therefore propose a model in which each of gp130, JAK and SOCS3 are directly bound to the other two, allowing SOCS3 to inhibit IL6 signalling with high potency and specificity.
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Affiliation(s)
- Jeffrey J Babon
- Walter and Eliza Hall Institute, Parkville, Australia; The University of Melbourne, Parkville, Australia.
| | - Leila N Varghese
- Walter and Eliza Hall Institute, Parkville, Australia; The University of Melbourne, Parkville, Australia
| | - Nicos A Nicola
- Walter and Eliza Hall Institute, Parkville, Australia; The University of Melbourne, Parkville, Australia
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Song XT, Aldrich M, Chen SY. Suppressor of cytokine signaling 1 inhibition strategy to enhance anti-HIV vaccination. Expert Rev Vaccines 2014; 5:495-503. [PMID: 16989630 DOI: 10.1586/14760584.5.4.495] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Extensive efforts aimed at stimulating immune responses by modifying HIV antigens and using various delivery systems and adjuvants have so far failed to generate promising HIV vaccines, highlighting the urgent need to explore alternative immunization approaches. Antigen-presenting cells, such as dendritic cells, play a critical role in the initiation and maintenance of immune responses against HIV infection and dendritic cells are regulated by stimulatory, as well as inhibitory signaling. Recent studies demonstrate that the suppressor of cytokine signaling 1 (SOCS1) functions as an antigen-presentation attenuator by restricting the Janus-activated kinase-signal transducers and activators of transcription and Toll-like receptor-signaling pathways. SOCS1-silenced dendritic cells produce higher levels of both T-helper 1- and 2-polarizing cytokines, broadly enhance memory HIV-specific B-cell and T-cell responses and activate natural killer cells owing to unbridled cytokine feedback signaling loops. Therefore, the inhibition of antigen-presentation attenuators represents a generally applicable and alternative strategy for enhancing the potency of various forms of prophylactic and therapeutic HIV vaccines.
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Affiliation(s)
- Xiao-Tong Song
- Baylor College of Medicine, Center for Cell and Gene Therapy, Department of Molecular and Human Genetics, Houston, TX 77030, USA.
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Shimada K, Serada S, Fujimoto M, Nomura S, Nakatsuka R, Harada E, Iwahori K, Tachibana I, Takahashi T, Kumanogoh A, Kishimoto T, Naka T. Molecular mechanism underlying the antiproliferative effect of suppressor of cytokine signaling-1 in non-small-cell lung cancer cells. Cancer Sci 2013; 104:1483-91. [PMID: 23962256 DOI: 10.1111/cas.12266] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 07/28/2013] [Accepted: 08/12/2013] [Indexed: 01/26/2023] Open
Abstract
Lung cancer (LC) is the major cause of death by cancer and the number of LC patients is increasing worldwide. This study investigated the therapeutic potential of gene delivery using suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of intracellular signaling pathways, for the treatment of LC. To examine the antitumor effect of SOCS-1 overexpression on non-small-cell lung cancer (NSCLC) cells, NSCLC cells (A549, LU65, and PC9) were infected with adenovirus-expressing SOCS-1 vector. The cell proliferation assay showed that A549 and LU65, but not PC9, were sensitive to SOCS-1 gene-mediated suppression of cell growth. Although JAK inhibitor I could also inhibit proliferation of A549 and LU65 cells, SOCS-1 gene delivery appeared to be more potent as SOCS-1 could suppress focal adhesion kinase and epidermal growth factor receptor, as well as the JAK/STAT3 signaling pathway. Enhanced phosphorylation of the p53 protein was detected by means of phospho-kinase array in SOCS-1 overexpressed A549 cells compared with control cells, whereas no phosphorylation of p53 was observed when JAK inhibitor I was used. Furthermore, treatment with adenoviral vector AdSOCS-1 in vivo significantly suppressed NSCLC proliferation in a xenograft model. These results suggest that the overexpression of SOCS-1 gene is effective for antitumor therapy by suppressing the JAK/STAT, focal adhesion kinase, and epidermal growth factor receptor signaling pathways and enhancing p53-mediated antitumor activity in NSCLC.
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Affiliation(s)
- Kazuki Shimada
- Laboratory for Immune Signal, National Institute of Biomedical Innovation, Osaka, Japan; Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan
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Trengove MC, Ward AC. SOCS proteins in development and disease. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL IMMUNOLOGY 2013; 2:1-29. [PMID: 23885323 PMCID: PMC3714205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 01/22/2013] [Indexed: 06/02/2023]
Abstract
Cytokine and growth factor signaling mediates essential roles in the differentiation, proliferation, survival and function of a number of cell lineages. This is achieved via specific receptors located on the surface of target cells, with ligand binding activating key intracellular signal transduction cascades to mediate the requisite cellular outcome. Effective resolution of receptor signaling is also essential, with excessive signaling having the potential for pathological consequences. The Suppressor of cytokine signaling (SOCS) family of proteins represent one important mechanism to extinguish cytokine and growth factor receptor signaling. There are 8 SOCS proteins in mammals; SOCS1-7 and the alternatively named Cytokine-inducible SH2-containing protein (CISH). SOCS1-3 and CISH are predominantly associated with the regulation of cytokine receptor signaling, while SOCS4-7 are more commonly involved in the control of Receptor tyrosine kinase (RTK) signaling. Individual SOCS proteins are typically induced by specific cytokines and growth factors, thereby generating a negative feedback loop. As a consequence of their regulatory properties, SOCS proteins have important functions in development and homeostasis, with increasing recognition of their role in disease, particularly their tumor suppressor and anti-inflammatory functions. This review provides a synthesis of our current understanding of the SOCS family, with an emphasis on their immune and hematopoietic roles.
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Affiliation(s)
- Monique C Trengove
- School of Medicine and Strategic Research Centre in Molecular & Medical Research, Deakin University Geelong, Victoria, Australia
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Subramaniam A, Shanmugam MK, Perumal E, Li F, Nachiyappan A, Dai X, Swamy SN, Ahn KS, Kumar AP, Tan BKH, Hui KM, Sethi G. Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2012; 1835:46-60. [PMID: 23103770 DOI: 10.1016/j.bbcan.2012.10.002] [Citation(s) in RCA: 150] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2012] [Revised: 10/18/2012] [Accepted: 10/21/2012] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis.
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Affiliation(s)
- Aruljothi Subramaniam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
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Guo CJ, Yang LS, Zhang YF, Wu YY, Weng SP, Yu XQ, He JG. A novel viral SOCS from infectious spleen and kidney necrosis virus: interacts with Jak1 and inhibits IFN-α induced Stat1/3 activation. PLoS One 2012; 7:e41092. [PMID: 22844427 PMCID: PMC3402483 DOI: 10.1371/journal.pone.0041092] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 06/17/2012] [Indexed: 11/18/2022] Open
Abstract
Interferon (IFN)-induced Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway is important in controlling immune responses and is negatively response-regulated by the suppressor of cytokine signaling (SOCS) proteins. However, several viruses have developed various strategies to inhibit this pathway to circumvent the anti-viral immunity of the host. The infectious spleen and kidney necrosis virus (ISKNV) is the type species of the genus Megalocytivirus in the family Iridoviridae and a causative agent of epizootics in fish. ISKNV ORF103R encodes a predicted viral SOCS (vSOCS) with high homology to the vertebrate SOCS1, but lacks a SOCS-box domain. Interestingly, vSOCS only exists in the genus Megalocytivirus. ISKNV-vSOCS can block the IFN-α-induced Jak/Stat pathway in HepG2 cells. Over-expression of ISKNV-vSOCS inhibited the activities of IFN-stimulated response element (ISRE) promoter; however, the inhibitions by ISKNV-vSOCS were dose-dependent. ISKNV-vSOCS interacted with Jak1 protein and inhibited its tyrosine kinase activity in vitro. ISKNV-vSOCS also impaired the phosphorylation of Stat1 and Stat3 proteins and suppressed their activations. The point mutations (F18D, S66A, S85A, and R64K) of ISKNV-vSOCS significantly impaired the inhibition of IFN-α-induced ISRE-promoter activation. In conclusion, vSOCS inhibits IFN-α-induced Stat1/Stat3 signaling, suggesting that Megalocytivirus has developed a novel strategy to evade IFN anti-viral immunity via vSOCS protein.
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Affiliation(s)
- Chang-Jun Guo
- MOE Key Laboratory of Aquatic Product Safety/State Key Laboratory for Biocontrol, School of Marine Science, Sun Yat-sen University, Guangzhou, PR China
- State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Li-Shi Yang
- State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Ying-Fen Zhang
- State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Yan-Yan Wu
- State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Shao-Ping Weng
- State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
| | - Xiao-Qiang Yu
- Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri, United States of America
| | - Jian-Guo He
- MOE Key Laboratory of Aquatic Product Safety/State Key Laboratory for Biocontrol, School of Marine Science, Sun Yat-sen University, Guangzhou, PR China
- State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
- * E-mail:
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Scheele C, Nielsen S, Kelly M, Broholm C, Nielsen AR, Taudorf S, Pedersen M, Fischer CP, Pedersen BK. Satellite cells derived from obese humans with type 2 diabetes and differentiated into myocytes in vitro exhibit abnormal response to IL-6. PLoS One 2012; 7:e39657. [PMID: 22761857 PMCID: PMC3383673 DOI: 10.1371/journal.pone.0039657] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Accepted: 05/24/2012] [Indexed: 01/08/2023] Open
Abstract
Obesity and type 2 diabetes are associated with chronically elevated systemic levels of IL-6, a pro-inflammatory cytokine with a role in skeletal muscle metabolism that signals through the IL-6 receptor (IL-6Rα). We hypothesized that skeletal muscle in obesity-associated type 2 diabetes develops a resistance to IL-6. By utilizing western blot analysis, we demonstrate that IL-6Rα protein was down regulated in skeletal muscle biopsies from obese persons with and without type 2 diabetes. To further investigate the status of IL-6 signaling in skeletal muscle in obesity-associated type 2 diabetes, we isolated satellite cells from skeletal muscle of people that were healthy (He), obese (Ob) or were obese and had type 2 diabetes (DM), and differentiated them in vitro into myocytes. Down-regulation of IL-6Rα was conserved in Ob myocytes. In addition, acute IL-6 administration for 30, 60 and 120 minutes, resulted in a down-regulation of IL-6Rα protein in Ob myocytes compared to both He myocytes (P<0.05) and DM myocytes (P<0.05). Interestingly, there was a strong time-dependent regulation of IL-6Rα protein in response to IL-6 (P<0.001) in He myocytes, not present in the other groups. Assessing downstream signaling, DM, but not Ob myocytes demonstrated a trend towards an increased protein phosphorylation of STAT3 in DM myocytes (P = 0.067) accompanied by a reduced SOCS3 protein induction (P<0.05), in response to IL-6 administration. Despite this loss of negative control, IL-6 failed to increase AMPKα2 activity and IL-6 mRNA expression in DM myocytes. There was no difference in fusion capacity of myocytes between cell groups. Our data suggest that negative control of IL-6 signaling is increased in myocytes in obesity, whereas a dysfunctional IL-6 signaling is established further downstream of IL-6Rα in DM myocytes, possibly representing a novel mechanism by which skeletal muscle function is compromised in type 2 diabetes.
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Affiliation(s)
- Camilla Scheele
- The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Centre, Rigshospitalet, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- * E-mail:
| | - Søren Nielsen
- The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Centre, Rigshospitalet, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Meghan Kelly
- The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Centre, Rigshospitalet, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christa Broholm
- The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Centre, Rigshospitalet, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anders Rinnov Nielsen
- The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Centre, Rigshospitalet, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sarah Taudorf
- The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Centre, Rigshospitalet, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Maria Pedersen
- The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Centre, Rigshospitalet, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christian P. Fischer
- The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Centre, Rigshospitalet, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bente Klarlund Pedersen
- The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Centre, Rigshospitalet, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Prchal-Murphy M, Semper C, Lassnig C, Wallner B, Gausterer C, Teppner-Klymiuk I, Kobolak J, Müller S, Kolbe T, Karaghiosoff M, Dinnyés A, Rülicke T, Leitner NR, Strobl B, Müller M. TYK2 kinase activity is required for functional type I interferon responses in vivo. PLoS One 2012; 7:e39141. [PMID: 22723949 PMCID: PMC3377589 DOI: 10.1371/journal.pone.0039141] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 05/20/2012] [Indexed: 01/25/2023] Open
Abstract
Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive (Tyk2K923E) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein’s stability. An inhibitory function was only observed upon over-expression of TYK2K923Ein vitro. Tyk2K923E mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors.
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Affiliation(s)
- Michaela Prchal-Murphy
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
| | - Christian Semper
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
| | - Caroline Lassnig
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
- Biomodels Austria, University of Veterinary Medicine, Vienna, Austria
| | - Barbara Wallner
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
| | - Christian Gausterer
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
| | | | - Julianna Kobolak
- Genetic Reprogramming Group Agricultural Biotechnology Center, Gödöllö, Hungary
| | - Simone Müller
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
| | - Thomas Kolbe
- Biomodels Austria, University of Veterinary Medicine, Vienna, Austria
- Department for Agrobiotechnology IFA Tulln, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Marina Karaghiosoff
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
| | - Andras Dinnyés
- Genetic Reprogramming Group Agricultural Biotechnology Center, Gödöllö, Hungary
- Molecular Animal Biotechnology Laboratory, Szent Istvan University, Gödöllö, Hungary
- BioTalentum Ltd., Gödöllö, Hungary
| | - Thomas Rülicke
- Biomodels Austria, University of Veterinary Medicine, Vienna, Austria
- Institute of Laboratory Animal Science, University of Veterinary Medicine, Vienna, Austria
| | - Nicole R. Leitner
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
| | - Birgit Strobl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
| | - Mathias Müller
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria
- Biomodels Austria, University of Veterinary Medicine, Vienna, Austria
- * E-mail:
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Iwahori K, Serada S, Fujimoto M, Ripley B, Nomura S, Mizuguchi H, Shimada K, Takahashi T, Kawase I, Kishimoto T, Naka T. SOCS-1gene delivery cooperates with cisplatin plus pemetrexed to exhibit preclinical antitumor activity against malignant pleural mesothelioma. Int J Cancer 2012; 132:459-71. [DOI: 10.1002/ijc.27611] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 04/16/2012] [Indexed: 01/29/2023]
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Ghanam RH, Samal AB, Fernandez TF, Saad JS. Role of the HIV-1 Matrix Protein in Gag Intracellular Trafficking and Targeting to the Plasma Membrane for Virus Assembly. Front Microbiol 2012; 3:55. [PMID: 22363329 PMCID: PMC3281212 DOI: 10.3389/fmicb.2012.00055] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Accepted: 02/01/2012] [Indexed: 11/13/2022] Open
Abstract
Human immunodeficiency virus type-1 (HIV-1) encodes a polypeptide called Gag that is able to form virus-like particles in vitro in the absence of any cellular or viral constituents. During the late phase of the HIV-1 infection, Gag polyproteins are transported to the plasma membrane (PM) for assembly. In the past two decades, in vivo, in vitro, and structural studies have shown that Gag trafficking and targeting to the PM are orchestrated events that are dependent on multiple factors including cellular proteins and specific membrane lipids. The matrix (MA) domain of Gag has been the focus of these studies as it appears to be engaged in multiple intracellular interactions that are suggested to be critical for virus assembly and replication. The interaction between Gag and the PM is perhaps the most understood. It is now established that the ultimate localization of Gag on punctate sites on the PM is mediated by specific interactions between the MA domain of Gag and phosphatidylinositol-4,5-bisphosphate [PI(4,5)P(2)], a minor lipid localized on the inner leaflet of the PM. Structure-based studies revealed that binding of PI(4,5)P(2) to MA induces minor conformational changes, leading to exposure of the myristyl (myr) group. Exposure of the myr group is also triggered by binding of calmodulin, enhanced by factors that promote protein self-association like the capsid domain of Gag, and is modulated by pH. Despite the steady progress in defining both the viral and cellular determinants of retroviral assembly and release, Gag's intracellular interactions and trafficking to its assembly sites in the infected cell are poorly understood. In this review, we summarize the current understanding of the structural and functional role of MA in HIV replication.
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Affiliation(s)
- Ruba H Ghanam
- Department of Microbiology, University of Alabama at Birmingham Birmingham, AL, USA
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36
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Souma Y, Nishida T, Serada S, Iwahori K, Takahashi T, Fujimoto M, Ripley B, Nakajima K, Miyazaki Y, Mori M, Doki Y, Sawa Y, Naka T. Antiproliferative effect of SOCS-1 through the suppression of STAT3 and p38 MAPK activation in gastric cancer cells. Int J Cancer 2011; 131:1287-96. [DOI: 10.1002/ijc.27350] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Accepted: 10/25/2011] [Indexed: 02/06/2023]
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Abstract
After central nervous system (CNS) injury axons fail to regenerate often leading to persistent neurologic deficit although injured peripheral nervous system (PNS) axons mount a robust regenerative response that may lead to functional recovery. Some of the failures of CNS regeneration arise from the many glial-based inhibitory molecules found in the injured CNS, whereas the intrinsic regenerative potential of some CNS neurons is actively curtailed during CNS maturation and limited after injury. In this review, the molecular basis for extrinsic and intrinsic modulation of axon regeneration within the nervous system is evaluated. A more complete understanding of the factors limiting axonal regeneration will provide a rational basis, which is used to develop improved treatments for nervous system injury.
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Affiliation(s)
- Toby A Ferguson
- Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA
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Piganis RAR, De Weerd NA, Gould JA, Schindler CW, Mansell A, Nicholson SE, Hertzog PJ. Suppressor of cytokine signaling (SOCS) 1 inhibits type I interferon (IFN) signaling via the interferon alpha receptor (IFNAR1)-associated tyrosine kinase Tyk2. J Biol Chem 2011; 286:33811-8. [PMID: 21757742 DOI: 10.1074/jbc.m111.270207] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Type I IFNs are critical players in host innate and adaptive immunity. IFN signaling is tightly controlled to ensure appropriate immune responses as imbalance could result in uncontrolled inflammation or inadequate responses to infection. It is therefore important to understand how type I IFN signaling is regulated. Here we have investigated the mechanism by which suppressor of cytokine signaling 1 (SOCS1) inhibits type I IFN signaling. We have found that SOCS1 inhibits type I IFN signaling not via a direct interaction with the IFN α receptor 1 (IFNAR1) receptor component but through an interaction with the IFNAR1-associated kinase Tyk2. We have characterized the residues/regions involved in the interaction between SOCS1 and Tyk2 and found that SOCS1 associates via its SH2 domain with conserved phosphotyrosines 1054 and 1055 of Tyk2. The kinase inhibitory region of SOCS1 is also essential for its interaction with Tyk2 and inhibition of IFN signaling. We also found that Tyk2 is preferentially Lys-63 polyubiquitinated and that this activation reaction is inhibited by SOCS1. The consequent effect of SOCS1 inhibition of Tyk2 not only results in a reduced IFN response because of inhibition of Tyk2 kinase-mediated STAT signaling but also negatively impacts IFNAR1 surface expression, which is stabilized by Tyk2.
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Affiliation(s)
- Rebecca A R Piganis
- Centre for Innate Immunity and Infectious Disease, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia
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Santos CI, Costa-Pereira AP. Signal transducers and activators of transcription-from cytokine signalling to cancer biology. Biochim Biophys Acta Rev Cancer 2011; 1816:38-49. [PMID: 21447371 DOI: 10.1016/j.bbcan.2011.03.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 03/17/2011] [Accepted: 03/22/2011] [Indexed: 10/18/2022]
Abstract
Signal transducers and activators of transcription (STATs) are, as the name indicates, both signal transducers and transcription factors. STATs are activated by cytokines and some growth factors and thus control important biological processes. These include cell growth, cell differentiation, apoptosis and immune responses. Dysregulation of STATs, either due to constitutive activation or function impairment, can have, therefore, deleterious biological consequences. This review places particular emphasis on their structural organization, biological activities and regulatory mechanisms most commonly utilized by cells to control STAT-mediated signalling. STATs also play important roles in cancer and immune deficiencies and are thus being exploited as therapeutic targets.
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Affiliation(s)
- Cristina Isabel Santos
- Imperial College London, Faculty of Medecine, Department of Surgery and Cancer, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK
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40
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O'Sullivan LA, Noor SM, Trengove MC, Lewis RS, Liongue C, Sprigg NS, Nicholson SE, Ward AC. Suppressor of cytokine signaling 1 regulates embryonic myelopoiesis independently of its effects on T cell development. THE JOURNAL OF IMMUNOLOGY 2011; 186:4751-61. [PMID: 21421851 DOI: 10.4049/jimmunol.1000343] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Suppressor of cytokine signaling 1 (SOCS1) has been shown to play important roles in the immune system. It acts as a key negative regulator of signaling via receptors for IFNs and other cytokines controlling T cell development, as well as Toll receptor signaling in macrophages and other immune cells. To gain further insight into SOCS1, we have identified and characterized the zebrafish socs1 gene, which exhibited sequence and functional conservation with its mammalian counterparts. Initially maternally derived, the socs1 gene showed early zygotic expression in mesodermal structures, including the posterior intermediate cell mass, a site of primitive hematopoiesis. At later time points, expression was seen in a broad anterior domain, liver, notochord, and intersegmental vesicles. Morpholino-mediated knockdown of socs1 resulted in perturbation of specific hematopoietic populations prior to the commencement of lymphopoiesis, ruling out T cell involvement. However, socs1 knockdown also lead to a reduction in the size of the developing thymus later in embryogenesis. Zebrafish SOCS1 was shown to be able to interact with both zebrafish Jak2a and Stat5.1 in vitro and in vivo. These studies demonstrate a conserved role for SOCS1 in T cell development and suggest a novel T cell-independent function in embryonic myelopoiesis mediated, at least in part, via its effects on receptors using the Jak2-Stat5 pathway.
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Affiliation(s)
- Lynda A O'Sullivan
- School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia
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41
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Kim K, Kim KH, Cheong J. Hepatitis B virus X protein impairs hepatic insulin signaling through degradation of IRS1 and induction of SOCS3. PLoS One 2010; 5:e8649. [PMID: 20351777 PMCID: PMC2843628 DOI: 10.1371/journal.pone.0008649] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2009] [Accepted: 11/18/2009] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is a major cause of chronic liver diseases, and frequently results in hepatitis, cirrhosis, and ultimately hepatocellular carcinoma. The role of HCV in associations with insulin signaling has been elucidated. However, the pathogenesis of HBV-associated insulin signaling remains to be clearly characterized. Therefore, we have attempted to determine the mechanisms underlying the HBV-associated impairment of insulin signaling. METHODOLOGY The expressions of insulin signaling components were investigated in HBx-transgenic mice, HBx-constitutive expressing cells, and transiently HBx-transfected cells. Protein and gene expression was examined by Western blot, immunohistochemistry, RT-PCR, and promoter assay. Protein-protein interaction was detected by coimmunoprecipitation. PRINCIPAL FINDINGS HBx induced a reduction in the expression of IRS1, and a potent proteasomal inhibitor blocked the downregulation of IRS1. Additionally, HBx enhanced the expression of SOCS3 and induced IRS1 ubiquitination. Also, C/EBPalpha and STAT3 were involved in the HBx-induced expression of SOCS3. HBx interfered with insulin signaling activation and recovered the insulin-mediated downregulation of gluconeogenic genes. CONCLUSIONS/SIGNIFICANCE These results provide direct experimental evidences for the contribution of HBx in the impairment of insulin signaling.
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Affiliation(s)
- KyeongJin Kim
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan, Republic of Korea
| | - Kook Hwan Kim
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan, Republic of Korea
| | - JaeHun Cheong
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan, Republic of Korea
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42
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Starr R, Fuchsberger M, Lau LS, Uldrich AP, Goradia A, Willson TA, Verhagen AM, Alexander WS, Smyth MJ. SOCS-1 binding to tyrosine 441 of IFN-gamma receptor subunit 1 contributes to the attenuation of IFN-gamma signaling in vivo. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2009; 183:4537-44. [PMID: 19734231 DOI: 10.4049/jimmunol.0901010] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Suppressor of cytokine signaling (SOCS)-1 is a critical inhibitor of IFN-gamma signal transduction in vivo, but the precise biochemical mechanism of action of SOCS-1 is unclear. Studies in vitro have shown that SOCS-1 binds to Jaks and inhibits their catalytic activity, but recent studies indicate SOCS-1 may act in a similar manner to SOCS-3 by firstly interacting with cytokine receptors and then inhibiting Jak activity. Here, we have generated mice, termed Ifngr1(441F), in which a putative SOCS-1 binding site, tyrosine 441 (Y441), on the IFN-gamma receptor subunit 1 (IFNGR1) is mutated. We confirm that SOCS-1 binds to IFNGR1 in wild-type but not mutant cells. Mutation of Y441 results in impaired negative regulation of IFN-gamma signaling. IFN-gamma-induced STAT1 activation is prolonged in Ifngr1(441F) cells, but not to the extent seen in cells completely lacking SOCS-1, suggesting that SOCS-1 maintains activity to modulate IFN-gamma signaling via other mechanisms. Despite this, we show that hypersensitivity to IFN-gamma results in enhanced innate tumor protection in Ifngr1(441F) mice in vivo, and unregulated expression of an IFN-gamma-dependent chemokine, monokine-induced by IFN-gamma. Collectively, these data indicate that Y441 contributes to the regulation of signaling through IFNGR1 via the recruitment of SOCS-1 to the receptor.
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MESH Headings
- Animals
- Cells, Cultured
- Gene Knock-In Techniques
- Interferon-gamma/deficiency
- Interferon-gamma/genetics
- Interferon-gamma/physiology
- Lung Neoplasms/genetics
- Lung Neoplasms/immunology
- Lung Neoplasms/secondary
- Melanoma, Experimental/genetics
- Melanoma, Experimental/immunology
- Melanoma, Experimental/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Protein Binding/genetics
- Protein Binding/immunology
- Protein Subunits/deficiency
- Protein Subunits/genetics
- Protein Subunits/metabolism
- Receptors, Interferon/deficiency
- Receptors, Interferon/genetics
- Receptors, Interferon/metabolism
- Signal Transduction/genetics
- Signal Transduction/immunology
- Suppressor of Cytokine Signaling 1 Protein
- Suppressor of Cytokine Signaling Proteins/deficiency
- Suppressor of Cytokine Signaling Proteins/genetics
- Suppressor of Cytokine Signaling Proteins/metabolism
- Tyrosine/genetics
- Tyrosine/metabolism
- Interferon gamma Receptor
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Affiliation(s)
- Robyn Starr
- Signal Transduction Laboratory, St Vincent's Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia.
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43
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Hale MB, Krutzik PO, Samra SS, Crane JM, Nolan GP. Stage dependent aberrant regulation of cytokine-STAT signaling in murine systemic lupus erythematosus. PLoS One 2009; 4:e6756. [PMID: 19707593 PMCID: PMC2727051 DOI: 10.1371/journal.pone.0006756] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2009] [Accepted: 07/21/2009] [Indexed: 02/07/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology that involves multiple interacting cell types driven by numerous cytokines and autoimmune epitopes. Although the initiating events leading to SLE pathology are not understood, there is a growing realization that dysregulated cytokine action on immune cells plays an important role in promoting the inflammatory autoimmune state. We applied phospho-specific flow cytometry to characterize the extent to which regulation of cytokine signal transduction through the STAT family of transcription factors is disturbed during the progression of SLE. Using a panel of 10 cytokines thought to have causal roles in the disease, we measured signaling responses at the single-cell level in five immune cell types from the MRLlpr murine model. This generated a highly multiplexed view of how cytokine stimuli are processed by intracellular signaling networks in adaptive and innate immune cells during different stages of SLE pathogenesis. We report that robust changes in cytokine signal transduction occur during the progression of SLE in multiple immune cell subtypes including increased T cell responsiveness to IL-10 and ablation of Stat1 responses to IFNalpha, IFNgamma, IL-6, and IL-21, Stat3 responses to IL-6, Stat5 responses to IL-15, and Stat6 responses to IL-4. We found increased intracellular expression of Suppressor of Cytokine Signaling 1 protein correlated with negative regulation of Stat1 responses to inflammatory cytokines. The results provide evidence of negative feedback regulation opposing inflammatory cytokines that have self-sustaining activities and suggest a cytokine-driven oscillator circuit may drive the periodic disease activity observed in many SLE patients.
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Affiliation(s)
- Matthew B. Hale
- The Baxter Laboratory of Genetic Pharmacology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Peter O. Krutzik
- The Baxter Laboratory of Genetic Pharmacology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Shamsher S. Samra
- The Baxter Laboratory of Genetic Pharmacology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Janelle M. Crane
- The Baxter Laboratory of Genetic Pharmacology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Garry P. Nolan
- The Baxter Laboratory of Genetic Pharmacology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America
- * E-mail:
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44
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Sharabi A, Sthoeger ZM, Mahlab K, Lapter S, Zinger H, Mozes E. A tolerogenic peptide that induces suppressor of cytokine signaling (SOCS)-1 restores the aberrant control of IFN-gamma signaling in lupus-affected (NZB x NZW)F1 mice. Clin Immunol 2009; 133:61-8. [PMID: 19631585 DOI: 10.1016/j.clim.2009.06.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2009] [Revised: 06/28/2009] [Accepted: 06/29/2009] [Indexed: 01/01/2023]
Abstract
Interferon-gamma (IFN-gamma) plays a pathogenic role in systemic lupus erythematosus (SLE). Uncontrolled IFN-gamma signaling may result from a deficiency in the negative regulator, namely, suppressor of cytokine signaling-1 (SOCS-1). We investigated the activation status of IFN-gamma signaling pathway in SLE-afflicted (New-Zealand-BlackxNew-Zealand-White)F1 mice and determined its responsiveness when treating with a tolerogenic peptide, hCDR1, which ameliorates SLE. SOCS-1 was suppressed and pSTAT1 was enhanced in spleen-derived cells from SLE-affected mice as compared with healthy controls. Treatment with hCDR1 reversed the expression of these two molecules in association with clinical amelioration. In vitro stimulation with IFN-gamma resulted in elevated levels of SOCS-1 in cells from both vehicle and hCDR1-treated mice but this effect reached significance only in cells of the latter group, which also exhibited reduced levels of pSTAT1. Thus, SOCS-1 is diminished in SLE-affected mice, and treatment with hCDR1 results in its up-regulation thereby restoring control of IFN-gamma signaling pathway.
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Affiliation(s)
- Amir Sharabi
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
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45
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DiGiandomenico A, Wylezinski LS, Hawiger J. Intracellular delivery of a cell-penetrating SOCS1 that targets IFN-gamma signaling. Sci Signal 2009; 2:ra37. [PMID: 19622834 PMCID: PMC2798805 DOI: 10.1126/scisignal.1162191] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Suppressor of cytokine signaling-1 (SOCS1) is an intracellular inhibitor of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that couples interferon-gamma (IFN-gamma) signaling to the nucleus. Because several inflammatory diseases are associated with uncontrolled IFN-gamma signaling, we engineered a recombinant cell-penetrating SOCS1 (CP-SOCS1) to target this pathway. Here, we show that CP-SOCS1, analogous to endogenous SOCS1, interacted with components of the IFN-gamma signaling complex and functionally attenuated the phosphorylation of STAT1, which resulted in the subsequent inhibition of the production of proinflammatory chemokines and cytokines. Thus, controlled, intracellular delivery of recombinant CP-SOCS1 boosted the anti-inflammatory potential of the cell by restoring the homeostatic balance between pro- and anti-inflammatory signaling. This approach to controlling signal transduction has potential use for therapeutic targeting of signaling pathways associated with inflammatory diseases.
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Affiliation(s)
- Antonio DiGiandomenico
- Department of Microbiology and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232–2363, USA
| | - Lukasz S. Wylezinski
- Department of Microbiology and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232–2363, USA
| | - Jacek Hawiger
- Department of Microbiology and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232–2363, USA
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RSV replication is attenuated by counteracting expression of the suppressor of cytokine signaling (SOCS) molecules. Virology 2009; 391:162-70. [PMID: 19595407 DOI: 10.1016/j.virol.2009.06.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2008] [Revised: 01/23/2009] [Accepted: 06/15/2009] [Indexed: 01/15/2023]
Abstract
Human RSV causes an annual epidemic of respiratory tract illness in infants and in elderly. Mechanisms by which RSV antagonizes IFN-mediated antiviral responses include inhibition of type I IFN mRNA transcription and blocking signal transduction of JAK/STAT family members. The suppressor of cytokines signaling (SOCS) gene family utilizes a feedback loop to inhibit cytokine responses and block the activation of the JAK/STAT signaling pathway. To evaluate the potential of SOCS molecules to subvert the innate immune response to RSV infection, eight SOCS family genes were examined. RSV infection up-regulated SOCS1, SOCS3, and CIS mRNA expression in HEp-2 cells. Suppression of SOCS1, SOCS3 and CIS by short interfering ribonucleic acid (siRNA) inhibited viral replication. Furthermore, inhibition of SOCS1, SOCS3, or CIS activated type I IFN signaling by inducing STAT1/2 phosphorylation. These results suggest that RSV infection escapes the innate antiviral response by inducing SOCS1, SOCS3 or CIS expression in epithelial cells.
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47
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Yang G, Badeanlou L, Bielawski J, Roberts AJ, Hannun YA, Samad F. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am J Physiol Endocrinol Metab 2009; 297:E211-24. [PMID: 19435851 PMCID: PMC2711669 DOI: 10.1152/ajpendo.91014.2008] [Citation(s) in RCA: 243] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Although obesity is associated with multiple features of the metabolic syndrome (insulin resistance, leptin resistance, hepatic steatosis, chronic inflammation, etc.), the molecular changes that promote these conditions are not completely understood. Here, we tested the hypothesis that elevated ceramide biosynthesis contributes to the pathogenesis of obesity and the metabolic syndrome. Chronic treatment for 8 wk of genetically obese (ob/ob), and, high-fat diet-induced obese (DIO) mice with myriocin, an inhibitor of de novo ceramide synthesis, decreased circulating ceramides. Decreased ceramide was associated with reduced weight, enhanced metabolism and energy expenditure, decreased hepatic steatosis, and improved glucose hemostasis via enhancement of insulin signaling in the liver and muscle. Inhibition of de novo ceramide biosynthesis decreased adipose expression of suppressor of cytokine signaling-3 (SOCS-3) and induced adipose uncoupling protein-3 (UCP3). Moreover, ceramide directly induced SOCS-3 and inhibited UCP3 mRNA in cultured adipocytes suggesting a direct role for ceramide in regulation of metabolism and energy expenditure. Inhibition of de novo ceramide synthesis had no effect on adipose tumor necrosis factor-alpha (TNF-alpha) expression but dramatically reduced adipose plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattactant protein-1 (MCP-1). This study highlights a novel role for ceramide biosynthesis in body weight regulation, energy expenditure, and the metabolic syndrome.
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Affiliation(s)
- Guang Yang
- Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA
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48
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Kim K, Kim HY, Son EJ, Heo J, Cheong J. Oleic acid inhibits hepatic insulin signaling through deregulation of STAT3 activation and C/EBPalpha expression. Cell Signal 2009; 21:1269-76. [PMID: 19332118 DOI: 10.1016/j.cellsig.2009.03.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2008] [Revised: 02/25/2009] [Accepted: 03/10/2009] [Indexed: 01/12/2023]
Abstract
Elevated free fatty acids (FFAs) are known to induce the impairment of insulin signaling. However, the insulin signaling components that are deregulated by FFAs in the liver remain unknown. Here, we examined the mechanisms of disruption of oleic acid on insulin signaling in hepatic cell lines. Oleic acid decreased the expression of insulin receptor substrate (IRS) 1 and augmented the expression of suppressor of cytokine signaling (SOCS) 3, which can induce the proteasome-mediated degradation of IRS. Moreover, oleic acid enhanced the phosphorylation of signal transducer and activator of transcription (STAT) 3 and induced the expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha). The interaction between STAT3 and C/EBPalpha was increased by oleic acid; these proteins subsequently enhanced the promoter activity of SOCS3 in the presence of oleic acid. Finally, oleic acid impaired the insulin signaling cascades through inhibition of the alpha-associated signaling pathway.
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Affiliation(s)
- Kyeongjin Kim
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea
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49
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Boyle K, Zhang JG, Nicholson SE, Trounson E, Babon JJ, McManus EJ, Nicola NA, Robb L. Deletion of the SOCS box of suppressor of cytokine signaling 3 (SOCS3) in embryonic stem cells reveals SOCS box-dependent regulation of JAK but not STAT phosphorylation. Cell Signal 2009; 21:394-404. [PMID: 19056487 PMCID: PMC3437335 DOI: 10.1016/j.cellsig.2008.11.002] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Accepted: 11/06/2008] [Indexed: 11/30/2022]
Abstract
The mechanism by which Suppressor of Cytokine Signaling-3 (SOCS3) negatively regulates cytokine signaling has been widely investigated using over-expression studies in cell lines and is thought to involve interactions with both the gp130 receptor and JAK1. Here, we compare the endogenous JAK/STAT signaling pathway downstream of Leukemia Inhibitory Factor (LIF) signaling in wild type (WT) Embryonic Stem (ES) cells and in ES cells lacking either the entire Socs3 gene or bearing a truncated form of SOCS3 (SOCS3DeltaSB) lacking the C-terminal SOCS box motif (SOCS3(DeltaSB/DeltaSB)). In SOCS3(DeltaSB/DeltaSB) cells phosphorylated JAK1 accumulated at much higher levels than in WT cells or even cells lacking SOCS3 (SOCS3(-/-)). In contrast enhanced activation of STAT3 and SHP2 was seen in SOCS3(-/-) cells. Size exclusion chromatography of cell extracts showed that in unstimulated cells, JAK1 was exclusively associated with receptors but following cytokine stimulation hyperphosphorylated JAK1 (pJAK1) appeared to dissociate from the receptor complex in a manner independent of SOCS3. In WT and SOCS3(DeltaSB/DeltaSB) cells SOCS3 was associated with pJAK1. The data suggest that dissociation of activated JAK1 from the receptor results in separate targeting of JAK1 for proteasomal degradation through a mechanism dependent on the SOCS3 SOCS box thus preventing further activation of STAT3.
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Affiliation(s)
- Kristy Boyle
- The Walter and Eliza Hall Institute, Parkville, Victoria 3050, Australia
| | - Jian Guo Zhang
- The Walter and Eliza Hall Institute, Parkville, Victoria 3050, Australia
| | | | - Evelyn Trounson
- The Walter and Eliza Hall Institute, Parkville, Victoria 3050, Australia
| | - Jeffery J. Babon
- The Walter and Eliza Hall Institute, Parkville, Victoria 3050, Australia
| | - Edward J. McManus
- The Walter and Eliza Hall Institute, Parkville, Victoria 3050, Australia
| | - Nicos A. Nicola
- The Walter and Eliza Hall Institute, Parkville, Victoria 3050, Australia
| | - Lorraine Robb
- The Walter and Eliza Hall Institute, Parkville, Victoria 3050, Australia
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Abstract
Cytokines are powerful mediators of the immune response that, following initial release by components of the innate system, drive effector functions as well as stimulate the additional arms of the response. Their individual functions are diverse, with stimulatory and inhibitory actions, with the resultant systemic immune response a summation of these actions. The frequently opposing effects of cytokines determine that the blockade of one results in the functional augmentation of the other. Thus, the differential regulation of cytokines profoundly influences the character of the immune response. The suppressor of cytokine signaling proteins are a family of molecules pivotal to this critical regulation. In this review, we will discuss their structural components and functions and our understanding of their impact on the systemic immune response.
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