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Borghol AH, Bitar ER, Hanna A, Naim G, Rahal EA. The role of Epstein-Barr virus in autoimmune and autoinflammatory diseases. Crit Rev Microbiol 2025; 51:296-316. [PMID: 38634723 DOI: 10.1080/1040841x.2024.2344114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/15/2024] [Accepted: 04/11/2024] [Indexed: 04/19/2024]
Abstract
Epstein-Barr Virus (EBV), a dsDNA herpesvirus, is believed to play a significant role in exacerbating and potentially triggering autoimmune and autoinflammatory maladies. Around 90% of the world is infected with the virus, which establishes latency within lymphocytes. EBV is also known to cause infectious mononucleosis, a self-limited flu-like illness, in adolescents. EBV is often reactivated and it employs several mechanisms of evading the host immune system. It has also been implicated in inducing host immune dysfunction potentially resulting in exacerbation or triggering of inflammatory processes. EBV has therefore been linked to a number of autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and Sjögren's syndrome. The review examines the molecular mechanisms through which the virus alters host immune system components thus possibly resulting in autoimmune processes. Understanding the mechanisms underpinning EBV-associated autoimmunity is pivotal; however, the precise causal pathways remain elusive. Research on therapeutic agents and vaccines for EBV has been stagnant for a long number of years until recent advances shed light on potential therapeutic targets. The implications of EBV in autoimmunity underscore the importance of developing targeted therapeutic strategies and, potentially, vaccines to mitigate the autoimmune burden associated with this ubiquitous virus.
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Affiliation(s)
- Abdul Hamid Borghol
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut, Lebanon
| | - Elio R Bitar
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut, Lebanon
| | - Aya Hanna
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut, Lebanon
| | - Georges Naim
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut, Lebanon
| | - Elias A Rahal
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut, Lebanon
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Zhang P, Pei B, Yi C, Akanyibah FA, Mao F. The role of suppressor of cytokine signaling 3 in inflammatory bowel disease and its associated colorectal cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167578. [PMID: 39571630 DOI: 10.1016/j.bbadis.2024.167578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/26/2024]
Abstract
Inflammatory bowel disease (IBD) and colorectal cancer (CRC), as two of the major human intestinal diseases, provide challenges for the medical field. Suppressor of cytokine signaling 3 (SOCS3), a protein molecule that negatively regulates cytokine signaling through multiple pathways, is involved in the regulation of various inflammatory diseases and tumors. In IBD, SOCS3 acts on a variety of cells to repair mucosal damage and balance the immune response, including epithelial cells, macrophages, dendritic cells, neutrophils, and T cells. In CRC, SOCS3 is inextricably linked to tumor cell proliferation, invasion, metastasis, and drug resistance. Therefore, it is crucial to systematically investigate the pathogenic involvement of SOCS3 in IBD and CRC. This article reviews the mechanisms and pathways by which SOCS3 is involved in the inhibition of IBD and the mitigation of CRC, and details the therapeutic options for targeting SOCS3.
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Affiliation(s)
- Pengfei Zhang
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu, PR China; Institute of Hematology, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian 223800, Jiangsu, PR China
| | - Chengxue Yi
- School of Medical Technology, Zhenjiang College, Zhenjiang 212028, PR China
| | - Francis Atim Akanyibah
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu, PR China
| | - Fei Mao
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu, PR China; Institute of Hematology, Jiangsu University, Zhenjiang 212013, Jiangsu, PR China.
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Cheng Y, Xiao S, Lan L, Liu D, Tang R, Gu J, Ma L, He Z, Chen X, Geng L, Chen P, Li H, Ren L, Zhu Y, Cheng Y, Gong S. WNT2B high‑expressed fibroblasts induce the fibrosis of IBD by promoting NK cells secreting IL-33. J Mol Med (Berl) 2024; 102:1199-1215. [PMID: 39138828 DOI: 10.1007/s00109-024-02477-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 08/15/2024]
Abstract
Fibrosis is an important pathological change in inflammatory bowel disease (IBD), but the mechanism has yet to be elucidated. WNT2B high‑expressed fibroblasts are enriched in IBD intestinal tissues, although the precise function of this group of fibroblasts remains unclear. This study investigated whether WNT2B high‑expressed fibroblasts aggravated intestinal tissue damage and fibrosis. Our study provides evidence that WNT2B high‑expressed fibroblasts and NK cells were enriched in colitis tissue of patients with IBD. WNT2B high‑expressed fibroblasts secreted wnt2b, which bound to FZD4 on NK cells and activated the NF-κB and STAT3 pathways to enhance IL-33 expression. TCF4, a downstream component of the WNT/β-catenin pathway, bound to p65 and promoted binding to IL-33 promoter. Furthermore, Salinomycin, an inhibitor of the WNT/β-catenin pathway, inhibited IL-33 secretion in colitis, thereby reducing intestinal inflammation.Knocking down WNT2B reduces NK cell infiltration and IL-33 secretion in colitis, and reduce intestinal inflammation and fibrosis. In conclusion, WNT2B high‑expressed fibroblasts activate NK cells by secreting wnt2b, which activates the WNT/β-catenin and NF-κB pathways to promote IL-33 expression and secretion, potentially culminating in the induction of colonic fibrosis in IBD. KEY MESSAGES: WNT2B high-expressed fibroblasts and NK cells are enriched in colitis tissue, promoting NK cells secreting IL-33. Wnt2b activates NF-κB and STAT3 pathways promotes IL-33 expression by activating p65 and not STAT3. syndrome TCF4 binds to p65 and upregulates the NF- κB pathway. Salinomycin reduces NK cell infiltration and IL-33 secretion in colitis. Knocking down WNT2B mitigates inflammation and fibrosis in chronic colitis.
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Affiliation(s)
- Yanling Cheng
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
- Department of Pediatrics, Shantou Central Hospital, Shantou, 515031, China
| | - Shuzhe Xiao
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Lin Lan
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Danqiong Liu
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
| | - Rui Tang
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
| | - Jianbiao Gu
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
| | - Li Ma
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
| | - Zhihua He
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
| | - Xirong Chen
- Nanshan School, Guangzhou Medical University, Guangzhou, 511436, China
| | - Lanlan Geng
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
| | - Peiyu Chen
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
| | - Huiwen Li
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
| | - Lu Ren
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China
| | - Yun Zhu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yang Cheng
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China.
| | - Sitang Gong
- Department of Digestive Diseases, Guangzhou Women and Children's Medical Center,Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510120, China.
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Beam TA, Klepser DG, Klepser ME, Bright DR, Klepser N, Schuring H, Wheeler S, Langerveld A. COVID-19 host genetic risk study conducted at community pharmacies: Implications for public health, research and pharmacists' scope of practice. Res Social Adm Pharm 2023; 19:1360-1364. [PMID: 37567834 PMCID: PMC10264161 DOI: 10.1016/j.sapharm.2023.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 03/06/2023] [Accepted: 06/10/2023] [Indexed: 08/13/2023]
Abstract
Community pharmacists serve a large, diverse population of patients, resulting in the potential to utilize community pharmacies as recruitment sites for clinical research. Beyond traditional roles as one of the most accessible health care professionals in the US healthcare system, pharmacists have played a major role in the response to the COVID-19 pandemic, administering hundreds of thousands of vaccines and tests. However, less emphasis is placed on the ability to leverage community pharmacies as research-focused partners for clinical studies. In this study, we demonstrate the feasibility and workflow of recruiting study participants from community pharmacies and confirm genetic markers of COVID-19 susceptibility. Specific genetic markers include those associated with COVID-19 infection risk (ACE2, TMEM27, and RAVER1), difficulty breathing (NOTCH4), and hospitalization (OAS3). In addition, collaboration with a clinical laboratory allowed for a more seamless consenting process without substantial training needs or workflow disruption at the community pharmacy site. The COVID-19 pandemic has demonstrated that the expansion of pharmacists' scope of practice is a key factor in managing the population health crisis; this study demonstrates that pharmacies can also advance clinical research studies by serving as sites for patient recruitment from a large, diverse, and ambulatory study population.
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Affiliation(s)
- Teresa A Beam
- Manchester University College of Pharmacy, Natural and Health Sciences 10627 Diebold Road, Fort Wayne, IN, 46845, USA.
| | - Donald G Klepser
- University of Nebraska Medical Center, 986120, Omaha, NE, 68198-6120, USA.
| | - Michael E Klepser
- Ferris State University College of Pharmacy, 1000 Oakland Drive, Kalamazoo, MI, 49008, USA.
| | - David R Bright
- Ferris State University College of Pharmacy, 220 Ferris Dr, Big Rapids, MI, 49307, USA.
| | - Nicklas Klepser
- Genemarkers, 126 East South Street, Kalamazoo, MI, 49007, USA; 15811 Louis Dr, Omaha, NE, 68118, USA.
| | - Hannah Schuring
- Genemarkers, 126 East South Street, Kalamazoo, MI, 49007, USA.
| | | | - Anna Langerveld
- Genemarkers, 126 East South Street, Kalamazoo, MI, 49007, USA.
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Yaobishu Regulates Inflammatory, Metabolic, Autophagic, and Apoptosis Pathways to Attenuate Lumbar Disc Herniation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3861380. [PMID: 35615578 PMCID: PMC9125431 DOI: 10.1155/2022/3861380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/18/2022] [Accepted: 04/16/2022] [Indexed: 12/03/2022]
Abstract
Objective Here, we aimed to explore the main mechanism of Yaobishu (YBS) in lumbar disc herniation (LDH). Methods and Results Eighteen compounds that might act on LDH were obtained through a combination of network pharmacology prediction and identification by high-performance liquid chromatography-mass spectrometry. The key compounds were palmitic acid and trans-4-hydroxy-3-methoxycinnamate (cinnamate). KEGG analysis demonstrated that palmitic acid target genes mainly regulate the PPAR signaling pathway, Ras signaling pathway, and fatty acid metabolism. Cinnamate target genes were primarily involved in chemical carcinogenesis-receptor activation, lipid and atherosclerosis, the HIF-1 signaling pathway, and nitrogen metabolism. The rat LDH model was constructed using autologous nucleus pulposus tissue implantation. Differential expression gene (DEGs) related to metabolism (CDKN1A and UHRF1), inflammation (S100A9 and SOCS3), autophagy (DCN and LEPR), and apoptosis (CTSW and BCL2A1) in dorsal root ganglion (DRG) tissues of the control and LDH groups was evaluated by RNA-Seq. TNF-α stimulated DRG neuronal cells were used to establish an in vitro LDH model. YBS, palmitic acid, and cinnamate reduced the expression of substance P, CGRP, S100A9, CTSW, and cleaved caspase-3, while enhancing the expression of CDKN1A, UHRF1, PCNA, Ki67, SOCS3, DCN, LEPR, and BCL2A1, as well as telomerase activity. Pearson's correlation analysis confirmed that DCN was positively correlated with BCL2A1, indicating that autophagy might be negatively correlated with apoptosis in LDH. YBS, palmitic acid, and cinnamate reduced the Siegal neurological score and serum IL-1β and IL-18 levels, while increasing changes in the hind paw mechanical withdrawal threshold. The RNA-Seq results further showed that YBS downregulated S100A9 and CTSW expression, while upregulating SOCS3, CDKN1A, UHRF1, DCN, LEPR, and BCL2A1 expression. Conclusion YBS and its compounds, palmitic acid, and cinnamate, attenuated LDH by regulating the inflammatory, metabolic, autophagic, and apoptotic pathways. Our results might improve the theoretical and experimental basis for clinical applications of LDH disease treatment.
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Integrated analysis of microbe-host interactions in Crohn’s disease reveals potential mechanisms of microbial proteins on host gene expression. iScience 2022; 25:103963. [PMID: 35479407 PMCID: PMC9035720 DOI: 10.1016/j.isci.2022.103963] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 12/11/2021] [Accepted: 02/18/2022] [Indexed: 12/15/2022] Open
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Devkota K, Murphy JM, Cowen LJ. GLIDE: combining local methods and diffusion state embeddings to predict missing interactions in biological networks. Bioinformatics 2021; 36:i464-i473. [PMID: 32657369 PMCID: PMC7355260 DOI: 10.1093/bioinformatics/btaa459] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Motivation One of the core problems in the analysis of biological networks is the link prediction problem. In particular, existing interactions networks are noisy and incomplete snapshots of the true network, with many true links missing because those interactions have not yet been experimentally observed. Methods to predict missing links have been more extensively studied for social than for biological networks; it was recently argued that there is some special structure in protein–protein interaction (PPI) network data that might mean that alternate methods may outperform the best methods for social networks. Based on a generalization of the diffusion state distance, we design a new embedding-based link prediction method called global and local integrated diffusion embedding (GLIDE). GLIDE is designed to effectively capture global network structure, combined with alternative network type-specific customized measures that capture local network structure. We test GLIDE on a collection of three recently curated human biological networks derived from the 2016 DREAM disease module identification challenge as well as a classical version of the yeast PPI network in rigorous cross validation experiments. Results We indeed find that different local network structure is dominant in different types of biological networks. We find that the simple local network measures are dominant in the highly connected network core between hub genes, but that GLIDE’s global embedding measure adds value in the rest of the network. For example, we make GLIDE-based link predictions from genes known to be involved in Crohn’s disease, to genes that are not known to have an association, and make some new predictions, finding support in other network data and the literature. Availability and implementation GLIDE can be downloaded at https://bitbucket.org/kap_devkota/glide. Supplementary information Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Kapil Devkota
- Department of Computer Science, Tufts University, Medford, MA 02155, USA
| | - James M Murphy
- Department of Mathematics, Tufts University, Medford, MA 02155, USA
| | - Lenore J Cowen
- Department of Computer Science, Tufts University, Medford, MA 02155, USA
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Cordes F, Foell D, Ding JN, Varga G, Bettenworth D. Differential regulation of JAK/STAT-signaling in patients with ulcerative colitis and Crohn's disease. World J Gastroenterol 2020; 26:4055-4075. [PMID: 32821070 PMCID: PMC7403801 DOI: 10.3748/wjg.v26.i28.4055] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/24/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
In 2018, the pan-Janus kinase (JAK) inhibitor tofacitinib was launched for the treatment of ulcerative colitis (UC). Although tofacitinib has proven efficacious in patients with active UC, it failed in patients with Crohn's disease (CD). This finding strongly hints at a different contribution of JAK signaling in both entities. Here, we review the current knowledge on the interplay between the JAK/signal transducer and activator of transcription (STAT) pathway and inflammatory bowel diseases (IBD). In particular, we provide a detailed overview of the differences and similarities of JAK/STAT-signaling in UC and CD, highlight the impact of the JAK/STAT pathway in experimental colitis models and summarize the published evidence on JAK/STAT-signaling in immune cells of IBD as well as the genetic association between the JAK/STAT pathway and IBD. Finally, we describe novel treatment strategies targeting JAK/STAT inhibition in UC and CD and comment on the limitations and challenges of the new drug class.
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Affiliation(s)
- Friederike Cordes
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster D-48149, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster D-48149, Germany
| | - John Nik Ding
- Department of Gastroenterology, St. Vincent’s Hospital, Melbourne 3002, Australia
- Department of Medicine, University of Melbourne, East Melbourne 3002, Australia
| | - Georg Varga
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster D-48149, Germany
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster D-48149, Germany
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Hou G, Bishu S. Th17 Cells in Inflammatory Bowel Disease: An Update for the Clinician. Inflamm Bowel Dis 2020; 26:653-661. [PMID: 31970388 PMCID: PMC11491631 DOI: 10.1093/ibd/izz316] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Indexed: 12/11/2022]
Abstract
Studies in humans strongly implicate Th17 cells in the pathogenesis of inflammatory bowel disease. Thus, Th17 cells are major targets of approved and emerging biologics. Herein, we review the role of Th17 in IBD with a clinical focus.
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Affiliation(s)
- Guoqing Hou
- Division of Gastroenterology, Department of Medicine, University of Michigan, MI, USA
| | - Shrinivas Bishu
- Crohn's and Colitis Center, Division of Gastroenterology, Department of Medicine, University of Michigan, MI, USA
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Hedl M, Sun R, Huang C, Abraham C. STAT3 and STAT5 Signaling Thresholds Determine Distinct Regulation for Innate Receptor-Induced Inflammatory Cytokines, and STAT3/ STAT5 Disease Variants Modulate These Outcomes. THE JOURNAL OF IMMUNOLOGY 2019; 203:3325-3338. [PMID: 31732533 DOI: 10.4049/jimmunol.1900031] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 10/17/2019] [Indexed: 01/21/2023]
Abstract
Genetic variants in the STAT3/STAT5A/STAT5B region are associated with immune-mediated diseases, including inflammatory bowel disease (IBD). However, how STAT3 and STAT5 regulate the critical balance between pro- and anti-inflammatory cytokines and how common disease-associated genetic variants (e.g., rs12942547) in the region modulate this balance are incompletely understood. We found that upon pattern-recognition receptor (PRR) stimulation of human monocyte-derived macrophages (MDMs), decreasing STAT3, STAT5a, and STAT5b expression led to a progressive decrease in anti-inflammatory cytokines, whereas proinflammatory cytokines initially decreased but then increased when STAT3 or STAT5 expression fell below a critical threshold. Mechanisms regulating STAT3- and STAT5-dependent inflammatory cytokine outcomes included negative feedback from autocrine/paracrine IL-10, TGF-β, IL-4, IL-13, IL-22, and TSLP secretion and SOCS1/SOCS2/SOCS3 induction. MDMs from rs12942547 AA disease-risk carriers demonstrated increased STAT3, STAT5a, and STAT5b expression and increased PRR-induced STAT3 and STAT5 phosphorylation relative to GG MDMs. Both pro- and anti-inflammatory cytokine secretion was decreased in MDMs from GG carriers, as STAT3, STAT5a, and STAT5b expression was above the threshold for reciprocal regulation of these cytokines. Taken together, we identify that the threshold of STAT3, STAT5a, and STAT5b expression determines if PRR-induced proinflammatory cytokines are increased or decreased, define mechanisms for this reciprocal regulation, and elucidate consequences for disease variants in the STAT3/STAT5A/STAT5B region, indicating that considering signaling thresholds and targeting specific cell types might be beneficial when evaluating therapeutic interventions in this pathway.
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Affiliation(s)
- Matija Hedl
- Department of Internal Medicine, Yale University, New Haven, CT 06510
| | - Rui Sun
- Department of Internal Medicine, Yale University, New Haven, CT 06510
| | - Chen Huang
- Department of Internal Medicine, Yale University, New Haven, CT 06510
| | - Clara Abraham
- Department of Internal Medicine, Yale University, New Haven, CT 06510
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STAT3 Genotypic Variant rs744166 and Increased Tyrosine Phosphorylation of STAT3 in IL-23 Responsive Innate Lymphoid Cells during Pathogenesis of Crohn's Disease. J Immunol Res 2019; 2019:9406146. [PMID: 31321245 PMCID: PMC6610725 DOI: 10.1155/2019/9406146] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/17/2019] [Accepted: 05/27/2019] [Indexed: 02/08/2023] Open
Abstract
Crohn's disease (CD) results from dysregulated immune responses to gut microbiota in genetically susceptible individuals, affecting multiple areas of the gastrointestinal tract. Innate lymphoid cells (ILCs) are tissue-resident innate effector lymphocytes which play crucial roles in mucosal immune defense, tissue repair, and maintenance of homeostasis. The accumulation of IFN-γ-producing ILC1s and increased level of proinflammatory cytokines produced by ILCs has been observed in the inflamed terminal ileum of CD patients. To date, the precise mechanisms of ILC plasticity and gene regulatory pathways in ILCs remain unclear. Signal transducer and activator of transcription 3 (STAT3) regulates gene expression in a cell-specific, cytokine-dependent manner, involving multiple immune responses. This study proposes the positive correlation between the prevalence of STAT3 rs744166 risky allele "A" with the severity of disease in a cohort of 94 CD patients. In addition, the results suggest an increased STAT3 activity in the inflamed ileum of CD patients, compared to unaffected ileum sections. Notably, IL-23 triggers the differentiation of CD117+NKp44- ILC3s and induces the activation of STAT3 in both CD117+NKp44- and CD117-NKp44- ILC subsets, implying the involvement of STAT3 in the initiation of ILC plasticity. Moreover, carriage of STAT3 "A" risk allele exhibited a higher basal level of STAT3 tyrosine phosphorylation, and an increased IL-23 triggered the pSTAT3 level. We also demonstrated that there was no delayed dephosphorylation of STAT3 in ILCs of both A/A and G/G donors. Overall, the results of this study suggest that IL-23-induced activation of STAT3 in the CD117-NKp44- ILC1s involves in ILC1-to-ILC3 plasticity and a potential regulatory role of ILC1 function. Those genetically susceptible individuals carried STAT3 rs744166 risky allele appear to have higher basal and cytokine-stimulated activation of STAT3 signal, leading to prolonged inflammation and chronic relapse.
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Liutkeviciene R, Vilkeviciute A, Kriauciuniene L, Deltuva VP. SIRT1 rs12778366, FGFR2 rs2981582, STAT3 rs744166, LIPC rs10468017, rs493258 and LPL rs12678919 genotypes and haplotype evaluation in patients with age-related macular degeneration. Gene 2019; 686:8-15. [DOI: 10.1016/j.gene.2018.11.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 10/11/2018] [Accepted: 11/01/2018] [Indexed: 02/08/2023]
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Sasaki-Iwaoka H, Taguchi K, Okada Y, Imamura E, Kubo S, Furukawa S, Morokata T. AS2762900-00, a potent anti-human IL-23 receptor monoclonal antibody, prevents epidermal hyperplasia in a psoriatic human skin xenograft model. Eur J Pharmacol 2019; 843:190-198. [PMID: 30472202 DOI: 10.1016/j.ejphar.2018.11.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 11/17/2018] [Accepted: 11/21/2018] [Indexed: 10/27/2022]
Abstract
Interleukin (IL)-23 is thought to be critical in the pathogenesis of psoriasis, and anti-IL-23 monoclonal antibodies (mAbs) have been approved for the treatment of psoriasis. We speculated that an anti-IL-23 receptor mAb might have greater efficacy than an anti-IL-23 mAb in the treatment of local inflamed lesions with high IL-23 levels. We previously generated an anti-human IL-23 receptor mAb, AS2762900-00, which potently blocked IL-23-induced cell proliferation, regardless of the concentration of IL-23. Here, we evaluated the therapeutic potential of AS2762900-00 in the treatment of psoriasis. Compared with untreated control, AS2762900-00 significantly reduced the epidermal thickness of lesions in a clinically relevant psoriatic human skin xenograft model. The expression of inflammatory genes including genes downstream of IL-23 signaling in the lesion tended to be lower in the AS2762900-00 group than the untreated group, suggesting that the inhibitory effects of AS2762900-00 in the psoriatic human skin xenograft model might occur via blockade of IL-23 signaling pathways. Further, AS2762900-00 showed an inhibitory effect on signal transducer and activator of transcription 3 (STAT3) phosphorylation as a downstream signal of IL-23 receptor activation in whole blood from patients with psoriasis. We also confirmed that AS2762900-00 inhibited IL-23-induced STAT3 phosphorylation in a concentration-dependent manner using whole blood from healthy donors. These data suggest that AS2762900-00 is a promising drug candidate for the treatment of psoriasis. In addition, STAT3 phosphorylation in whole blood may be a useful biomarker for the evaluation of the pharmacodynamic effects of AS2762900-00 in healthy volunteers in clinical development.
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Affiliation(s)
- Haruna Sasaki-Iwaoka
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
| | - Katsunari Taguchi
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Yohei Okada
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Emiko Imamura
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Satoshi Kubo
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Shigetada Furukawa
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
| | - Tatsuaki Morokata
- Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
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14
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Bakhtiar S, Fekadu J, Seidel MG, Gambineri E. Allogeneic Hematopoietic Stem Cell Transplantation for Congenital Immune Dysregulatory Disorders. Front Pediatr 2019; 7:461. [PMID: 31799221 PMCID: PMC6865355 DOI: 10.3389/fped.2019.00461] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 10/23/2019] [Indexed: 12/30/2022] Open
Abstract
Primary immunodeficiency disorders that predominantly affect immune regulation and mechanisms of self-tolerance have come into the limelight, because at least for a subgroup of monogenetic disorders, a targeted therapy has become available. Nevertheless, their management often involves the treatment of severely compromising, refractory, multi-organ autoimmunity, leading to further increased susceptibility to infections and complications of long-term immune suppressive treatment, including the risk of malignancy. While evidence for allogeneic hematopoietic stem cell transplantation (alloHSCT) as a curative treatment option for severely affected patients by this disease category accumulates, clear indications, and guidelines for alloHSCT are lacking. Predictive and stratification-relevant tools such as disease activity scores are largely missing and often there is not a consistent genotype-phenotype correlation within the same family to facilitate the decision whether to transplant or not. In this review, we provide a literature-based update on indications and outcomes of alloHSCT for congenital immune dysregulative inborn errors of immunity according to the IUIS classification 2017.
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Affiliation(s)
- Shahrzad Bakhtiar
- Division for Pediatric Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt, Germany
| | - Julia Fekadu
- Division for Pediatric Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt, Germany
| | - Markus G Seidel
- Research Unit for Pediatric Hematology and Immunology, Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria
| | - Eleonora Gambineri
- NEUROFARBA Department, University of Florence, University of Florence, Florence, Italy.,Haematology-Oncology Department, Anna Meyer Children's Hospital, Florence, Italy
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15
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Targeted Gene Sequencing in Children with Crohn's Disease and Their Parents: Implications for Missing Heritability. G3-GENES GENOMES GENETICS 2018; 8:2881-2888. [PMID: 30166421 PMCID: PMC6118318 DOI: 10.1534/g3.118.200404] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Crohn’s disease is a complex genetic trait characterized by chronic relapsing intestinal inflammation. Genome wide association studies (GWAS) have identified more than 170 loci associated with the disease, accounting for ∼14% of the disease variance. We hypothesized that rare genetic variation in GWAS positional candidates also contribute to disease pathogenesis. We performed targeted, massively-parallel sequencing of 101 genes in 205 children with Crohn’s disease, including 179 parent-child trios and 200 controls, both of European ancestry. We used the gene burden test implemented in VAAST and estimated effect sizes using logistic regression and meta-analyses. We identified three genes with nominally significant p-values: NOD2, RTKN2, and MGAT3. Only NOD2 was significant after correcting for multiple comparisons. We identified eight novel rare variants in NOD2 that are likely disease-associated. Incorporation of rare variation and compound heterozygosity nominally increased the proportion of variance explained from 0.074 to 0.089. We estimated the population attributable risk and total heritability of variation in NOD2 to be 32.9% and 3.4%, respectively, with 3.7% and 0.25% accounted for by rare putatively functional variants. Sequencing probands (as opposed to genotyping) to identify rare variants and incorporating phase by sequencing parents can recover a portion of the missing heritability of Crohn’s disease.
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16
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Kvedaraite E, Lourda M, Ideström M, Chen P, Olsson-Åkefeldt S, Forkel M, Gavhed D, Lindforss U, Mjösberg J, Henter JI, Svensson M. Tissue-infiltrating neutrophils represent the main source of IL-23 in the colon of patients with IBD. Gut 2016; 65:1632-41. [PMID: 26160381 DOI: 10.1136/gutjnl-2014-309014] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 06/18/2015] [Indexed: 12/19/2022]
Abstract
OBJECTIVE In IBD, interleukin-23 (IL-23) and its receptor (IL-23R) are implicated in disease initiation and progression. Novel insight into which cells produce IL-23 at the site of inflammation at an early stage of IBD will promote the development of new tools for diagnosis, treatment and patient monitoring. We examined the cellular source of IL-23 in colon tissue of untreated newly diagnosed paediatric patients with IBD. DESIGN Colon tissues from IBD and non-IBD patients were analysed by quantitative real-time PCR (qPCR), immunofluorescence confocal microscopy and flow cytometry after appropriate sample preparation. Blood samples from IBD and non-IBD patients and healthy controls were analysed using flow cytometry and qPCR. RESULTS We discovered that tissue-infiltrating neutrophils were the main source of IL-23 in the colon of paediatric patients with IBD, while IL-23(+) human leucocyte antigen-DR(+) or IL-23(+)CD14(+) cells were scarce or non-detectable, respectively. The colonic IL-23(+) neutrophils expressed C-X-C motif (CXC)R1 and CXCR2, receptors for the CXC ligand 8 (CXCL8) chemokine family, and a corresponding CXCR1(+)CXCR2(+)IL-23(+)subpopulation of neutrophils was also identified in the blood of both patients with IBD and healthy individuals. However, CXCL8-family chemokines were only elevated in colon tissue from patients with IBD. CONCLUSIONS This study provides the first evidence of CXCR1(+)CXCR2(+)IL-23-producing neutrophils that infiltrate and accumulate in inflamed colon tissue of patients with IBD. Thus, this novel source of IL-23 may play a key role in disease progression and will be important to take into consideration in the development of future strategies to monitor, treat and prevent IBD.
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Affiliation(s)
- Egle Kvedaraite
- Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Magda Lourda
- Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Maja Ideström
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Puran Chen
- Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Selma Olsson-Åkefeldt
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Marianne Forkel
- Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Désirée Gavhed
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Ulrik Lindforss
- Department of Clinical Science, Gastromedical Center, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Jenny Mjösberg
- Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Jan-Inge Henter
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Mattias Svensson
- Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
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Abstract
PURPOSE OF REVIEW Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor involved in a wide variety of cellular functions. Germline loss-of-function mutations are known to cause hyper-IgE immunodeficiency (autosomal dominant hyper IgE syndrome), whereas somatic gain-of-function mutations have been described in large granular cell leukemia, and polymorphisms in STAT3 have been associated with inflammatory bowel disease and other solid organ tumors. The review examines recent discoveries in our understanding of the nonmalignant disease processes affected by STAT3 mutations in human disease. RECENT FINDINGS Germline STAT3 gain-of-function mutations have recently been identified in patients with an early-onset autoimmunity/lymphoproliferative syndrome. STAT3 plays a previously unrecognized role in several facets of the pathogenesis of allergy. Loss-of-function STAT3 mutations revealed critical roles for STAT3 in the development and function of several lymphocyte populations and in their role in host defense. SUMMARY The discovery of new gain-of-function mutations in STAT3, as well as new studies among patients with loss-of-function mutations, expand the understanding of the pathophysiology of STAT3 function and its importance in regulating the immune system. These findings contribute to elucidating STAT3 biology and clinical symptoms in patients with the different disease phenotypes.
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18
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FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice. Nat Commun 2016; 7:11314. [PMID: 27066907 PMCID: PMC4832079 DOI: 10.1038/ncomms11314] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 03/11/2016] [Indexed: 02/07/2023] Open
Abstract
FNDC4 is a secreted factor sharing high homology with the exercise-associated myokine irisin (FNDC5). Here we report that Fndc4 is robustly upregulated in several mouse models of inflammation as well as in human inflammatory conditions. Specifically, FNDC4 levels are increased locally at inflamed sites of the intestine of inflammatory bowel disease patients. Interestingly, administration of recombinant FNDC4 in the mouse model of induced colitis markedly reduces disease severity compared with mice injected with a control protein. Conversely, mice lacking Fndc4 develop more severe colitis. Analysis of binding of FNDC4 to different immune cell types reveals strong and specific binding to macrophages and monocytes. FNDC4 treatment of bone marrow-derived macrophages in vitro results in reduced phagocytosis, increased cell survival and reduced proinflammatory chemokine expression. Hence, treatment with FNDC4 results in a state of dampened macrophage activity, while enhancing their survival. Thus, we have characterized FNDC4 as a factor with direct therapeutic potential in inflammatory bowel disease and possibly other inflammatory diseases. FDNC4 is a poorly characterized homologue of FNDC5/irisin, a myokine induced by exercise. Here the authors show that FDNC4 increases macrophage survival in growth factor deprivation, inhibits phagocytosis and transcriptional responses to M1 and M2 polarizing stimuli, and protects mice from DSS-induced colitis.
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19
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Van Der Kraak L, Langlais D, Jothy S, Beauchemin N, Gros P. Mapping hyper-susceptibility to colitis-associated colorectal cancer in FVB/NJ mice. Mamm Genome 2016; 27:213-24. [PMID: 26979842 DOI: 10.1007/s00335-016-9625-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 02/25/2016] [Indexed: 11/24/2022]
Abstract
Inbred strains of mice differ in susceptibility to colitis-associated colorectal cancer (CA-CRC). We tested 10 inbred strains of mice for their response to azoxymethane/dextran sulfate sodium-induced CA-CRC and identified a bimodal inter-strain distribution pattern when tumor multiplicity was used as a phenotypic marker of susceptibility. The FVB/NJ strain was particularly susceptible showing a higher tumor burden than any other susceptible strains (12.5-week post-treatment initiation). FVB/NJ hyper-susceptibility was detected as early as 8-week post-treatment initiation with FVB/NJ mice developing 5.5-fold more tumors than susceptible A/J or resistant B6 control mice. Linkage analysis by whole genome scan in informative (FVB/NJ×C3H/HeJ)F2 mice identified a novel susceptibility locus designated as C olon c ancer s usceptibility 6 (Ccs6) on proximal mouse chromosome 6. When gender was used as a covariate, a LOD score of 5.4 was computed with the peak marker being positioned at rs13478727, 43.8 Mbp. Mice homozygous for FVB/NJ alleles at this locus had increased tumor multiplicity compared to homozygous C3H/HeJ mice. Positional candidates in this region of chromosome 6 were analyzed with respect to a possible role in carcinogenesis and a role in inflammatory response using a new epigenetic gene scoring tool (Myeloid Inflammation Score).
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Affiliation(s)
- Lauren Van Der Kraak
- Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada
| | - David Langlais
- Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada
| | - Serge Jothy
- Department of Laboratory Medicine and Pathology, St. Michael's Hospital and University of Toronto, Toronto, ON, M5B 1W8, Canada
| | - Nicole Beauchemin
- Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.,Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada
| | - Philippe Gros
- Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada. .,Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada.
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20
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Leppkes M, Neurath MF, Herrmann M, Becker C. Immune deficiency vs. immune excess in inflammatory bowel diseases-STAT3 as a rheo-STAT of intestinal homeostasis. J Leukoc Biol 2015; 99:57-66. [PMID: 26232455 DOI: 10.1189/jlb.5mr0515-221r] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 07/02/2015] [Indexed: 12/17/2022] Open
Abstract
Genome-wide association studies have provided many genetic alterations, conferring susceptibility to multifactorial polygenic diseases, such as inflammatory bowel diseases. Yet, how specific genetic alterations functionally affect intestinal inflammation often remains elusive. It is noteworthy that a large overlap of genes involved in immune deficiencies with those conferring inflammatory bowel disease risk has been noted. This has provided new arguments for the debate on whether inflammatory bowel disease arises from either an excess or a deficiency in the immune system. In this review, we highlight the functional effect of an inflammatory bowel disease-risk allele, which cannot be deduced from genome-wide association studies data alone. As exemplified by the transcription factor signal transducer and activator of transcription 3 (STAT3), we show that a single gene can have a plethora of effects in various cell types of the gut. These effects may individually contribute to the restoration of intestinal homeostasis on the one hand or pave the way for excessive immunopathology on the other, as an inflammatory "rheo-STAT".
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Affiliation(s)
- Moritz Leppkes
- *Medical Clinic 1 and Medical Clinic 3, University Clinic, Friedrich Alexander University, Erlangen, Germany
| | - Markus F Neurath
- *Medical Clinic 1 and Medical Clinic 3, University Clinic, Friedrich Alexander University, Erlangen, Germany
| | - Martin Herrmann
- *Medical Clinic 1 and Medical Clinic 3, University Clinic, Friedrich Alexander University, Erlangen, Germany
| | - Christoph Becker
- *Medical Clinic 1 and Medical Clinic 3, University Clinic, Friedrich Alexander University, Erlangen, Germany
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21
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22
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Zhang J, Wu J, Peng X, Song J, Wang J, Dong W. Associations between STAT3 rs744166 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a meta-analysis. PLoS One 2014; 9:e109625. [PMID: 25286337 PMCID: PMC4186844 DOI: 10.1371/journal.pone.0109625] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Accepted: 09/09/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Many studies have investigated the associations between the signal transducer and activator of transcription 3 (STAT3) in the susceptibility to ulcerative colitis (UC) and Crohn's disease (CD). However, the results remain inconsistent. This meta-analysis determined the risk of STAT3 rs744166 polymorphism-conferred UC and CD susceptibility. MATERIALS AND METHODS Electronic databases, including PubMed, EMBASE and the Cochrane Library, were searched for all eligible studies that evaluated the association between STAT3 rs744166 polymorphisms with UC and CD risk up to August 21, 2014. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using fixed- or random-effects models. RESULTS Twelve studies containing 10298 patients with CD, 4244 patients with UC and 11191 controls were included in this meta-analysis. The results indicated that the STAT3 rs744166 polymorphism was associated with CD and UC susceptibility (CD: GA+AA vs. GG, OR = 1.20, 95%CI, 1.11-1.30, I2 = 0%, Punadjusted<0.00001, PBonferroni<0.00005, PFDR<0.00001; UC: GA+AA vs. GG, OR = 1.21, 95%CI, 1.08-1.36, I2 = 1%, Punadjusted = 0.001, PBonferroni = 0.005, PFDR = 0.00125). In subgroup analyses by ethnicity, the significant association was found only among Caucasians. However, when grouped by age of onset, positive associations were found both among adults and children. In addition, when stratified by study design and genotyping methods, the risk of CD was significantly associated with the STAT3 rs744166 polymorphism in hospital-based and population-based groups and in SNP Array and SNPlex groups. For UC, significant associations were also found in population-based, PCR-RFLP and SNPlex groups. Moreover, these findings were sufficiently robust to withstand the Bonferroni correction and false discovery rate (FDR). CONCLUSION This meta-analysis indicates that carriers of the STAT3 rs744166 'A' allele have a significantly greater risk of CD and UC, especially among Caucasians.
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Affiliation(s)
- Jixiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Jianhong Wu
- Wuhan medical treatment center, Wuhan, Hubei Province, China
| | - Xiulan Peng
- Department of Oncology, The Fifth Hospital of Wuhan, Wuhan, Hubei Province, China
| | - Jia Song
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Jun Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- * E-mail:
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23
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Jastroch M, Morin S, Tschöp MH, Yi CX. The hypothalamic neural-glial network and the metabolic syndrome. Best Pract Res Clin Endocrinol Metab 2014; 28:661-71. [PMID: 25256762 DOI: 10.1016/j.beem.2014.02.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Despite numerous educational interventions and biomedical research efforts, modern society continues to suffer from obesity and its associated metabolic diseases, such as type 2 diabetes mellitus, and these diseases show little sign of abating. One reason for this is an incomplete understanding of the pathology of the metabolic syndrome, which obstructs the development of effective therapeutic strategies. While hypothalamic neuropathy is a potential candidate that may contribute to the pathogenesis of the metabolic syndrome, the specific causes of hypothalamic neuropathy remain largely unknown. During different stages of high-calorie diet-induced metabolic syndrome, the hypothalamus undergoes gliosis and angiogenesis, both of which potentially reflect ongoing inflammatory processes. This overview discusses current data suggesting a role for hypothalamic inflammation-like processes in diet-induced metabolic diseases and provides a perspective on how to unravel molecular mechanisms of "hypothalamic inflammation" in order to develop anti-obesity therapeutic strategies.
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Affiliation(s)
- Martin Jastroch
- Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment & Technische Universität München, Munich 85748, Germany
| | - Silke Morin
- Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment & Technische Universität München, Munich 85748, Germany
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment & Technische Universität München, Munich 85748, Germany
| | - Chun-Xia Yi
- Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment & Technische Universität München, Munich 85748, Germany.
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24
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Wick EC, Rabizadeh S, Albesiano E, Wu X, Wu S, Chan J, Rhee KJ, Ortega G, Huso DL, Pardoll D, Housseau F, Sears CL. Stat3 activation in murine colitis induced by enterotoxigenic Bacteroides fragilis. Inflamm Bowel Dis 2014; 20:821-34. [PMID: 24704822 PMCID: PMC4121853 DOI: 10.1097/mib.0000000000000019] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Enterotoxigenic Bacteroides fragilis (ETBF), a molecular subclass of the common human commensal, B. fragilis, has been associated with inflammatory bowel disease. ETBF colitis is characterized by the activation of Stat3 and a Th17 immune response in the colonic mucosa. This study was designed to investigate the time course and cellular distribution of Stat3 activation in ETBF-colonized mice. METHODS C57BL/6 wild-type, C57BL/6, or Rag-1 mice were inoculated with saline, nontoxigenic B. fragilis or ETBF. Histologic diagnosis and mucosal Stat activation (immunohistochemistry, Western blot, and/or electrophorectic mobility shift assay) were evaluated over time (6-24 h, 1-7 d, and 1-18 mo after inoculation). Mucosal permeability was evaluated at 16 hours, 1 day, and 3 days. Mucosal immune responses were evaluated at 1 week, and 12 and 18 months. RESULTS ETBF induced rapid-onset colitis that persisted for up to 1 year. Stat3 activation (pStat3) was noted in the mucosal immune cells within 16 hours, with colonic epithelial cell activation evident at 24 hours after inoculation. ETBF-induced increased mucosal permeability was first observed at 24 hours after inoculation, after which the initial immune cell pStat3 activation was noted. Immune cell pStat3 was present in the absence of epithelial pStat3 (C57BL/6). Epithelial pStat3 was present in the absence of T and B cells (Rag-1 mice). pStat3 persisted in the epithelial and immune cells for 1 year, characterized by isolated pStat3-positive cell clusters, with varying intensity distributed through the proximal and distal colon. Similarly, mucosal Th17 immune responses persisted for up to 1 year. Loss of fecal ETBF colonization was associated with the loss of mucosal pStat3 and Th17 immune responses. CONCLUSIONS ETBF rapidly induces immune cell pStat3, which is independent of epithelial pStat3. This occurs before ETBF-induced mucosal permeability, suggesting that ETBF, likely through B. fragilis toxin and its action on the colonic epithelial cell, triggers mucosal immune cell Stat3 activation. Peak mucosal Stat3 activation (immune and epithelial cells) occurs subsequently when other colonic bacteria may contribute to the ETBF-initiated immune response due to barrier dysfunction. ETBF induces long-lived, focal colonic Stat3 activation and Th17 immune responses dependent on the ongoing ETBF colonization. Further study is needed to evaluate the early mucosal signaling events, resulting in epithelial Stat3 activation and the sequelae of long-term colonic Stat3 activation.
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Affiliation(s)
- Elizabeth C. Wick
- Department of Surgery, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Shervin Rabizadeh
- Department of Pediatrics, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California
| | - Emilia Albesiano
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - XinQun Wu
- Department of Medicine, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Shaoguang Wu
- Department of Medicine, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - June Chan
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Ki-Jong Rhee
- Department of Medicine, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
- Department of Biomedical Laboratory Science, Yonsei University, Wonju, Republic of Korea
| | - Guillermo Ortega
- Department of Medicine, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - David L. Huso
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Drew Pardoll
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
- Department of Medicine, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Franck Housseau
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Cynthia L. Sears
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
- Department of Medicine, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
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25
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Fujita N, Oritani K, Ichii M, Yokota T, Saitoh N, Okuzaki D, Sekine Y, Kon S, Muromoto R, Saitoh K, Yoshimura A, Matsuda T, Kanakura Y. Signal-transducing adaptor protein-2 regulates macrophage migration into inflammatory sites during dextran sodium sulfate induced colitis. Eur J Immunol 2014; 44:1791-801. [PMID: 24733425 DOI: 10.1002/eji.201344239] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 01/16/2014] [Accepted: 03/13/2014] [Indexed: 12/31/2022]
Abstract
Signal-transducing adaptor protein-2 (STAP-2) was cloned as a c-fms/M-CSF receptor interacting protein. STAP-2 is an adaptor protein carrying pleckstrin homology and Src homology 2 like domains, as well as a YXXQ motif. STAP-2 has been indicated to have an ability to bind and modulate a variety of signaling and transcriptional molecules. Especially, our previous in vitro studies showed that STAP-2 is crucial for immune and/or inflammatory responses. Here, we have investigated the role of STAP-2 in intestinal inflammation in vivo. The disruption of STAP-2 attenuates dextran sodium sulfate induced colitis via inhibition of macrophage recruitment. To study whether hematopoietic or epithelial cell derived STAP-2 is required for this phenomenon, we generated BM chimeric mice. STAP-2-deficient macrophages impair the ability of CXCL12-induced migration. Intriguingly, STAP-2 also regulates production of proinflammatory chemokines and cytokines such as CXCL1 and TNF-α from intestinal epithelial cells. Therefore, STAP-2 has a potential to regulate plural molecular events during pathological inflammatory responses. Furthermore, our findings not only indicate that STAP-2 is important in regulating intestinal inflammation, but also provide new insights toward the development of novel therapeutic approaches.
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Affiliation(s)
- Natsuko Fujita
- Department of Hematology and Oncology, Osaka University Graduate School of medicine, Osaka, Japan
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Russo RC, Garcia CC, Teixeira MM, Amaral FA. The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases. Expert Rev Clin Immunol 2014; 10:593-619. [DOI: 10.1586/1744666x.2014.894886] [Citation(s) in RCA: 317] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Stevic MS, Stefanic M, Tokic S, Glavas-Obrovac L, Mihaljevic S, Karner I. Pilot study of variants of the IL-23R and STAT3 genes reveals no association with Hashimoto's thyroiditis in the Croatian population. Endocr Res 2014; 39:164-7. [PMID: 24460100 DOI: 10.3109/07435800.2013.875038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Interleukin-23 receptor (IL-23R) and signal transducer and activator of transcription 3 (STAT3) polymorphisms are common risk factors for a number of T helper (Th) 17-mediated autoimmune diseases. However, the importance of genetic variations in Th17 pathways to thyroid autoimmunity, and particularly Hashimoto's thyroiditis (HT), is not fully understood. In this study, we genotyped three single nucleotide polymorphisms (SNPs) within the IL-23R (rs11209026/p.Arg381Gln, rs7530511) and STAT3 (rs744166) genes in 217 Croatian patients with HT and 161 healthy controls using fluorescence resonance energy transfer technology and melting curve analysis of polymerase chain reaction products. None of the tested SNPs or IL-23R haplotypes was associated with HT susceptibility or disease severity. These results suggest that the studied IL-23R/STAT3 polymorphisms affecting Th17 signaling efficiency are not major determinants of HT risk in the Croatian population. Further work is necessary to determine if these loci contribute modestly or conditionally to the risk of HT.
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Affiliation(s)
- Mirjana Suver Stevic
- Clinical Institute of Nuclear Medicine and Radiation Protection, Osijek University Hospital , Osijek , Croatia
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Koukos G, Polytarchou C, Kaplan JL, Morley-Fletcher A, Gras-Miralles B, Kokkotou E, Baril-Dore M, Pothoulakis C, Winter HS, Iliopoulos D. MicroRNA-124 regulates STAT3 expression and is down-regulated in colon tissues of pediatric patients with ulcerative colitis. Gastroenterology 2013; 145:842-52.e2. [PMID: 23856509 PMCID: PMC4427058 DOI: 10.1053/j.gastro.2013.07.001] [Citation(s) in RCA: 188] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Revised: 07/02/2013] [Accepted: 07/03/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Altered levels and functions of microRNAs (miRs) have been associated with inflammatory bowel diseases (IBDs), although little is known about their roles in pediatric IBD. We investigated whether colonic mucosal miRs are altered in children with ulcerative colitis (UC). METHODS We used a library of 316 miRs to identify those that regulate phosphorylation of signal transducer and activator of transcription 3 (STAT3) in NCM460 human colonocytes incubated with interleukin-6. Levels of miR-124 were measured by real-time polymerase chain reaction analysis of colon biopsies from pediatric and adult patients with UC and patients without IBD (controls), and of HCT-116 colonocytes incubated with 5-aza-2'-deoxycytidine (5-AZA). Methylation of the MIR124 promoter was measured by quantitative methylation-specific polymerase chain reaction. RESULTS Levels of phosphorylated STAT3 and the genes it regulates (encoding vascular endothelial growth factor (VEGF), BCL2, BCLXL, and matrix metallopeptidase 9 [MMP9]) were increased in pediatric patients with UC compared with control tissues. Overexpression of miR-124, let-7, miR-125, miR-26, or miR-101 reduced STAT3 phosphorylation by ≥ 75% in NCM460 cells; miR-124 had the greatest effect. miR-124 was down-regulated specifically in colon tissues from pediatric patients with UC and directly targeted STAT3 messenger RNA (mRNA). Levels of miR-124 were decreased, whereas levels of STAT3 phosphorylation increased in colon tissues from pediatric patients with active UC compared with those with inactive disease. In addition, levels of miR-124 and STAT3 were inversely correlated in mice with experimental colitis. Down-regulation of miR-124 in tissues from children with UC was attributed to hypermethylation of its promoter region. Incubation of HCT-116 colonocytes with 5-AZA up-regulated miR-124 and reduced levels of STAT3 mRNA. CONCLUSIONS miR-124 appears to regulate the expression of STAT3. Reduced levels of miR-124 in colon tissues of children with active UC appear to increase expression and activity of STAT3, which could promote inflammation and the pathogenesis of UC in children.
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Affiliation(s)
- Georgios Koukos
- Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA,Institute for Molecular Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA,Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA
| | - Christos Polytarchou
- Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA,Institute for Molecular Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA,Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA
| | - Jess L. Kaplan
- Pediatric IBD Center, Mass General Hospital for Children, Boston, MA
| | | | - Beatriz Gras-Miralles
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Efi Kokkotou
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Mariah Baril-Dore
- Pediatric IBD Center, Mass General Hospital for Children, Boston, MA
| | - Charalabos Pothoulakis
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA
| | - Harland S. Winter
- Pediatric IBD Center, Mass General Hospital for Children, Boston, MA
| | - Dimitrios Iliopoulos
- Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA,Institute for Molecular Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA,Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA,Corresponding author: Dimitrios Iliopoulos, Ph.D., Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, 650 Charles E. Young Dr. South, CHS 44-133, Los Angeles, CA 90095-7278. Tel: 310-825-8856;
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Nieminen JK, Niemi M, Sipponen T, Salo HM, Klemetti P, Färkkilä M, Vakkila J, Vaarala O. Dendritic cells from Crohn's disease patients show aberrant STAT1 and STAT3 signaling. PLoS One 2013; 8:e70738. [PMID: 23950992 PMCID: PMC3737363 DOI: 10.1371/journal.pone.0070738] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Accepted: 06/26/2013] [Indexed: 12/31/2022] Open
Abstract
Abnormalities of dendritic cells (DCs) and STAT proteins have been reported in Crohn’s disease (CD). Studies on JAK/STAT signaling in DCs are, however, lacking in CD. We applied a flowcytometric single-cell-based phosphoepitope assay to evaluate STAT1 and STAT3 pathways in DC subsets from CD patients. In addition, circulating DC counts were determined, together with the activation-related immunophenotype. We found that IL-6- and IFN-α-induced STAT3 phosphorylation and IFN-α-induced STAT1 phosphorylation were impaired in plasmacytoid DCs (pDCs) from CD patients (P = 0.005, P = 0.013, and P = 0.006, respectively). In myeloid DCs (mDCs), IFN-α-induced STAT1 and STAT3 phosphorylation were attenuated (P<0.001 and P = 0.048, respectively), but IL-10-induced STAT3 phosphorylation was enhanced (P = 0.026). IFN-γ-induced STAT1 signaling was intact in both DC subtypes. Elevated plasma IL-6 levels were detected in CD (P = 0.004), which strongly correlated with disease activity (ρ = 0.690, P<0.001) but not with IL-6-induced STAT3 phosphorylation. The numbers of pDCs and BDCA3+ mDCs were decreased, and CD40 expression on CD1c+ mDCs was increased in CD. When elucidating the effect of IL-6 signaling on pDC function, we observed that IL-6 treatment of healthy donor pDCs affected the maturation of and modified the T-cell priming by pDCs, favoring Th2 over Th1 type of response and the expression of IL-10 in T cells. Our results implicate DC signaling in human CD. Reduced IL-6 responsiveness in pDCs, together with the attenuated IFN-α-induced signaling in both DC subtypes, may contribute to the immunological dysregulation in CD patients.
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Affiliation(s)
- Janne K Nieminen
- Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland.
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Jurickova I, Collins MH, Chalk C, Seese A, Bezold R, Lake K, von Allmen D, Frischer JS, Falcone RA, Trapnell BC, Denson LA. Paediatric Crohn disease patients with stricturing behaviour exhibit ileal granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody production and reduced neutrophil bacterial killing and GM-CSF bioactivity. Clin Exp Immunol 2013; 172:455-65. [PMID: 23600834 DOI: 10.1111/cei.12076] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2013] [Indexed: 01/17/2023] Open
Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies are associated with stricturing behaviour in Crohn disease (CD). We hypothesized that CD ileal lamina propria mononuclear cells (LPMC) would produce GM-CSF autoantibodies and peripheral blood (PB) samples would contain GM-CSF neutralizing capacity (NC). Paediatric CD and control PBMC and ileal biopsies or LPMC were isolated and cultured and GM-CSF, immunoglobulin (Ig)G and GM-CSF autoantibodies production were measured by enzyme-linked immunosorbent assay (ELISA). Basal and GM-CSF-primed neutrophil bacterial killing and signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation (pSTAT5) were measured by flow cytometry. GM-CSF autoantibodies were enriched within total IgG for LPMC isolated from CD ileal strictures and proximal margins compared to control ileum. Neutrophil bacterial killing was reduced in CD patients compared to controls. Within CD, neutrophil GM-CSF-dependent STAT5 activation and bacterial killing were reduced as GM-CSF autoantibodies increased. GM-CSF stimulation of pSTAT5 did not vary between controls and CD patients in washed PB granulocytes in which serum was removed. However, GM-CSF stimulation of pSTAT5 was reduced in whole PB samples from CD patients. These data were used to calculate the GM-CSF NC. CD patients with GM-CSF NC greater than 25% exhibited a fourfold higher rate of stricturing behaviour and surgery. The likelihood ratio (95% confidence interval) for stricturing behaviour for patients with elevation in both GM-CSF autoantibodies and GM-CSF NC was equal to 5 (2, 11). GM-CSF autoantibodies are produced by LPMC isolated from CD ileal resection specimens and are associated with reduced neutrophil bacterial killing. CD peripheral blood contains GM-CSF NC, which is associated with increased rates of stricturing behaviour.
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Affiliation(s)
- I Jurickova
- Department of Pediatrics Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Willson TA, Jurickova I, Collins M, Denson LA. Deletion of intestinal epithelial cell STAT3 promotes T-lymphocyte STAT3 activation and chronic colitis following acute dextran sodium sulfate injury in mice. Inflamm Bowel Dis 2013; 19:512-25. [PMID: 23429443 PMCID: PMC4330009 DOI: 10.1097/mib.0b013e31828028ad] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intestinal epithelial cell (IEC) STAT3 is required for wound healing following acute dextran sodium sulfate (DSS) injury. We hypothesized that loss of IEC STAT3 would promote the development of chronic colitis following acute DSS injury. METHODS Colitis was induced in IEC-specific STAT3-deficient mice (STAT3)[INCREMENT]IEC and littermate controls (STAT3 Flx/Flx) with 4% DSS for 7 days, followed by water consumption for 21 days. Epithelial and immune mediators and severity of colitis were determined. RESULTS Survival, colon length, and histologic injury were significantly worse at day 28 in STAT3[INCREMENT]IEC mice. IEC proliferation and apoptosis did not vary by genotype at day 14 or day 28. The colonic lamina propria frequency of pSTAT3* cells was increased at day 28 and correlated with histologic injury in STAT3 [INCREMENT]IEC mice. The frequency of colonic F480* pSTAT3* macrophages and CD3* pSTAT3* T lymphocytes were increased in STAT3[INCREMENT]IEC mice as compared with STAT3 Flx/Flx controls. In STAT3[INCREMENT]IEC mice, colonic expression of STAT3 target genes Reg3β and Reg3γ, which mediate epithelial restitution, were significantly decreased, whereas expression of interleukin (IL)-17a, IFNγ, CXCL2, CXCL10, and CCL2 were significantly increased and correlated with the increase in histologic severity at day 28(P < 0.05). IL-17a expression also correlated with the increased lamina propria frequency of CD3* pSTAT3* T lymphocytes. CONCLUSIONS Loss of intestinal epithelial STAT3 leads to more severe chronic inflammation following acute injury, which is not accounted for by a sustained defect in epithelial proliferation or apoptosis 7 or 21 days after 1 cycle of DSS but rather defective REG3 expression and expansion of pSTAT3* lymphocytes and IL-17A expression.
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Affiliation(s)
- Tara A. Willson
- Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH,Cancer and Cell Biology Program, the University of Cincinnati College of Medicine, Cincinnati, OH
| | - Ingrid Jurickova
- Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Margaret Collins
- Pathology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Lee A. Denson
- Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH,Cancer and Cell Biology Program, the University of Cincinnati College of Medicine, Cincinnati, OH,to whom correspondence should be addressed: MLC 2010, 3333 Burnet Avenue, Cincinnati, OH 45229, Tel: 513-636-7575, Fax: 513-636-5581,
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Abstract
INTRODUCTION STAT3 is a key transcription factor for many regulatory factors that modulate gene transcription. Particularly important are cytokines and growth factors that maintain homeostasis by regulating immunocytes, stromal and epithelial cells. Dysregulation of STAT3 by constitutive activation plays an important role in the initiation of inflammation and cellular transformation in numerous cancers, especially of epithelial origin. This review focuses on STAT3 drive in gastric cancer initiation and progression, with emphasis on its activation by cytokines, and how targeting the primary drivers or gastric STAT3 therapeutically may prevent or slow stomach cancer development. AREAS COVERED This review will discuss the mechanics of STAT3 signalling, how constitutive STAT3 activation promotes gastric tumourigenesis in both human adenocarcinomas and mouse models, the nature of the upstream regulators of STAT3, and their association with chronic Helicobacter pylori infection, STAT3-activated genes that promote transformation and progression, and finally the development and use of STAT3 and upstream cytokine inhibitors as therapeutics. EXPERT OPINION Chronic STAT3 activation is a key event in gastric cancer induction and progression. Specific targeting of stomach epithelial STAT3 or blocking IL-11Rα/gp130 and/or EGFR signal transduction in chronic gastric inflammation and metaplasia may be therapeutically effective in preventing gastric carcinogenesis.
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Affiliation(s)
- Andrew S Giraud
- Murdoch Childrens Research Institute, Royal Childrens Hospital, Parkville, Australia.
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