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Zhu S, Lin Y, Ding Z. Exploring inflammatory bowel disease therapy targets through druggability genes: a Mendelian randomization study. Front Immunol 2024; 15:1352712. [PMID: 38707907 PMCID: PMC11069403 DOI: 10.3389/fimmu.2024.1352712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 04/08/2024] [Indexed: 05/07/2024] Open
Abstract
Background Inflammatory bowel disease is an incurable group of recurrent inflammatory diseases of the intestine. Mendelian randomization has been utilized in the development of drugs for disease treatment, including the therapeutic targets for IBD that are identified through drug-targeted MR. Methods Two-sample MR was employed to explore the cause-and-effect relationship between multiple genes and IBD and its subtypes ulcerative colitis and Crohn's disease, and replication MR was utilized to validate this causality. Summary data-based Mendelian randomization analysis was performed to enhance the robustness of the outcomes, while Bayesian co-localization provided strong evidential support. Finally, the value of potential therapeutic target applications was determined by using the estimation of druggability. Result With our investigation, we identified target genes associated with the risk of IBD and its subtypes UC and CD. These include the genes GPBAR1, IL1RL1, PRKCB, and PNMT, which are associated with IBD risk, IL1RL1, with a protective effect against CD risk, and GPX1, GPBAR1, and PNMT, which are involved in UC risk. Conclusion In a word, this study identified several potential therapeutic targets associated with the risk of IBD and its subtypes, offering new insights into the development of therapeutic agents for IBD.
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Affiliation(s)
| | | | - Zhen Ding
- Department of Hepatobiliary Surgery, Chaohu Hospital of Anhui Medical University, Hefei, China
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Büttner J, Blüthner E, Greif S, Kühl A, Elezkurtaj S, Ulrich J, Maasberg S, Jochum C, Tacke F, Pape UF. Predictive Potential of Biomarkers of Intestinal Barrier Function for Therapeutic Management with Teduglutide in Patients with Short Bowel Syndrome. Nutrients 2023; 15:4220. [PMID: 37836505 PMCID: PMC10574292 DOI: 10.3390/nu15194220] [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: 08/18/2023] [Revised: 09/12/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
INTRODUCTION The human intestinal tract reacts to extensive resection with spontaneous intestinal adaptation. We analyzed whether gene expression analyses or intestinal permeability (IP) testing could provide biomarkers to describe regulation mechanisms in the intestinal barrier in short bowel syndrome (SBS) patients during adaptive response or treatment with the glucagon-like peptide-2 analog teduglutide. METHODS Relevant regions of the GLP-2 receptor gene were sequenced. Gene expression analyses and immunohistochemistry were performed from mucosal biopsies. IP was assessed using a carbohydrate oral ingestion test. RESULTS The study includes 59 SBS patients and 19 controls. Increases in gene expression with teduglutide were received for sucrase-isomaltase, sodium/glucose cotransporter 1, and calcium/calmodulin serine protein kinase. Mannitol recovery was decreased in SBS but elevated with teduglutide (Δ 40%), showed a positive correlation with remnant small bowel and an inverse correlation with parenteral support. CONCLUSIONS Biomarkers predicting clinical and functional features in human SBS are very limited. Altered specific gene expression was shown for genes involved in nutrient transport but not for genes controlling tight junctions. However, mannitol recovery proved useful in describing the absorptive capacity of the gut during adaptation and treatment with teduglutide.
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Affiliation(s)
- Janine Büttner
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow Klinikum, 10117 Berlin, Germany; (E.B.); (S.G.); (C.J.); (F.T.)
| | - Elisabeth Blüthner
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow Klinikum, 10117 Berlin, Germany; (E.B.); (S.G.); (C.J.); (F.T.)
- Berlin Institute of Health (BIH), 10178 Berlin, Germany
| | - Sophie Greif
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow Klinikum, 10117 Berlin, Germany; (E.B.); (S.G.); (C.J.); (F.T.)
| | - Anja Kühl
- iPATH.Berlin, Core Unit der Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt, Campus Benjamin Franklin, 12203 Berlin, Germany;
| | - Sefer Elezkurtaj
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Pathology, Campus Mitte, 10117 Berlin, Germany;
| | - Jan Ulrich
- Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, 20099 Hamburg, Germany; (J.U.); (S.M.)
| | - Sebastian Maasberg
- Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, 20099 Hamburg, Germany; (J.U.); (S.M.)
| | - Christoph Jochum
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow Klinikum, 10117 Berlin, Germany; (E.B.); (S.G.); (C.J.); (F.T.)
| | - Frank Tacke
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow Klinikum, 10117 Berlin, Germany; (E.B.); (S.G.); (C.J.); (F.T.)
| | - Ulrich-Frank Pape
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow Klinikum, 10117 Berlin, Germany; (E.B.); (S.G.); (C.J.); (F.T.)
- Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, 20099 Hamburg, Germany; (J.U.); (S.M.)
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Zhao J, Lin Z, Ying P, Zhao Z, Yang H, Qian J, Gong Y, Zhou Y, Dai Y, Jiao Y, Zhu W, Wang H, Tang L. circSMAD4 promotes experimental colitis and impairs intestinal barrier functions by targeting JAK2 through sponging miR-135a-5p. J Crohns Colitis 2022; 17:593-613. [PMID: 36239525 DOI: 10.1093/ecco-jcc/jjac154] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Numerous studies have explored the association between circular RNAs (circRNAs) and Crohn's disease (CD). However, the pathological role, biological functions, and molecular mechanisms of circRNAs in CD have not been fully elucidated. METHODS The circRNA microarray analysis was performed to identify deregulated circRNAs in colon tissues. The identified circRNA were verified through quantitative real time-polymerase chain reaction (qRT-PCR). In vivo and in vitro functional studies were performed to verify the role of circSMAD4 in CD and investigate the mechanisms involved. RESULTS We found that circSMAD4 was the most significantly upregulated circRNA. The expression level of circSMAD4 was positively correlated with levels of inflammatory factors. Overexpression of circSMAD4 impaired tight junction (TJ) proteins and enhanced apoptosis of epithelial cells. These effects were reversed by treatment with miR-135a-5p mimic. Mechanistic studies showed that circSMAD4 exerts its effects on CD by "sponging" miR-135a-5p to regulate Janus kinase 2 (JAK2). Si-circSMAD4 delivery through microspheres ameliorated experimental colitis and protected the intestinal barrier function in IL-10 knock-out mice. CONCLUSION This study shows that circSMAD4 regulates the progression of experimental colitis via the miR-135a-5p/JAK2 signaling axis and it may be a potential therapeutic target.
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Affiliation(s)
- Jie Zhao
- Department of Gastrointestinal Surgery and and Central Laboratory, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Zhiliang Lin
- Department of Colorectal Disease, Intestinal Microenvironment Treatment Center, Shanghai Tenth People's Hospital, Tenth People's Hospital of Tongji University
| | - Pu Ying
- Department of Orthopedics, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine
| | - Zhibin Zhao
- Department of Gastroenterology, Taizhou People's Hospital Affiliated to Nanjing Medical University
| | - Haojun Yang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Jun Qian
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yu Gong
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yan Zhou
- Department of Gastrointestinal Surgery and and Central Laboratory, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yi Dai
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Yuwen Jiao
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University
| | - Honggang Wang
- Department of General Surgery, Taizhou People's Hospital Affiliated to Nanjing Medical University
| | - Liming Tang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University
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The Role of Genetic Factors in the Development of Acute Respiratory Viral Infection COVID-19: Predicting Severe Course and Outcomes. Biomedicines 2022; 10:biomedicines10030549. [PMID: 35327350 PMCID: PMC8945420 DOI: 10.3390/biomedicines10030549] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/11/2022] [Accepted: 02/16/2022] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to identify single nucleotide variants in genes associated with susceptibility to or severe outcomes of COVID-19. A total of 319 genomic DNA samples from patients with varying degrees of disease severity and 78 control DNA samples from people who had regular or prolonged contact with patients with COVID-19 but did not have clinical manifestations and/or antibodies to SARS-CoV-2. Seven SNPs were identified that were statistically associated with disease risk or severe course, rs1799864 in the CCR2 gene (OR = 2.21), rs1990760 in the IFIH1 gene (OR = 2.41), rs1800629 in the TNF gene (OR = 1.98), rs75603675 in the TMPRSS2 gene (OR = 1.86), rs7842 in the C3AR1 gene (OR = 2.08), rs179008 in the gene TLR7 (OR = 1.85), rs324011 in the C3AR1 gene (OR = 2.08), rs179008 in the TLR7 gene (OR = 1.85), and rs324011 in the STAT6 gene (OR = 1.84), as well as two variants associated with protection from COVID-19, rs744166 in the STAT3 gene (OR = 0.36) and rs1898830 in the TLR2 gene (OR = 0.47). The genotype in the region of these markers can be the criterion of the therapeutic approach for patients with COVID-19.
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Wang L, Feng Y, Wang J, Luo T, Wang X, Wu M, Wang R, Chen D, Li J, Wang J. Arbutin Ameliorates Murine Colitis by Inhibiting JAK2 Signaling Pathway. Front Pharmacol 2021; 12:683818. [PMID: 34594215 PMCID: PMC8477021 DOI: 10.3389/fphar.2021.683818] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 09/01/2021] [Indexed: 12/26/2022] Open
Abstract
Background and objective: Abnormal activation of Janus kinase 2 (JAK2) promotes the pathogenesis and progress of inflammatory bowel disease (IBD) by stimulating the cytokine traffic. Based on docking studies, arbutin, a natural product extracted from a traditional medicinal plant bearberry, was found to bind to JAK2. The study aimed to investigate the effects and mechanisms of regulating JAK2 by arbutin on colitis in mice. Methods: A mice colitis model was established to mimic human IBD. The mice freely drank water containing dextran sulfate sodium. Inflammation in epithelial (IEC6) and immune (RAW264.7) cells was analyzed following treatment with lipopolysaccharides (LPS). Results: Colitis symptoms, including body weight loss, increased disease activity index, and increased colon weight/length ratio, were significantly alleviated by arbutin. Mediators of colonic pro-inflammatory cytokines as well as apoptosis markers in colitis were suppressed by the glycoside. High expression of phosphorylated JAK2 in colitis was significantly reversed by arbutin. The effects of arbutin treatment on colitis were considerably inhibited by the JAK2 inhibitor AG490. LPS-induced inflammatory responses were also suppressed by arbutin, which was notably inhibited by the JAK2 inhibitor AG490. Conclusion: The findings obtained herein suggest the protective role of arbutin and provide novel insights into alternative colitis treatments, which involve inhibition of the JAK2 signaling pathway.
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Affiliation(s)
- Liang Wang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, China.,Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Yuntao Feng
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, China
| | - Jianwen Wang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, China
| | - Tenglong Luo
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, China
| | - Xinyue Wang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, China
| | - Mengze Wu
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, China
| | - Runxia Wang
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, China
| | - Dapeng Chen
- Comparative Medicine Department of Researching and Teaching, Dalian Medical University, Dalian, China
| | - Jiyan Li
- Department of Spleen and Stomach, Dalian Hospital of Traditional Chinese Medicine, Dalian, China
| | - Jingyu Wang
- Laboratory Animal Center, Dalian Medical University, Dalian, China
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Abstract
The Janus kinase (JAK), signal transducer of activation (STAT) pathway, discovered by investigating interferon gene induction, is now recognized as an evolutionary conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. Since its discovery, this pathway has become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors such as cytokines and hormones, mediate their diverse functions. The understanding of JAK-STAT signaling in the intestine has not only impacted basic science research, particularly in the understanding of intercellular communication and cell-extrinsic control of gene expression, but it has also become a prototype for transition of bench to bedside research, culminating in the clinical implementation of pathway-specific therapeutics.
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Mager R, Roda G, Shalaby MK, Vetrano S. Fibrotic Strictures in Crohn's Disease: Mechanisms and Predictive Factors. Curr Drug Targets 2021; 22:241-251. [PMID: 33081672 DOI: 10.2174/1389450121666201020160803] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/13/2020] [Accepted: 08/27/2020] [Indexed: 11/22/2022]
Abstract
Fibrotic strictures are one of the most severe complications of Crohn's Disease (CD). They occur in about 50% of patients at five years and in 70% at ten years of the diagnosis. The only treatment available for symptomatic fibrotic strictures is surgical resection and endoscopic dilation. Both strategies are associated with a high rate of recurrence, and with multiple surgical resections, which pose the threat of surgical morbidity and short bowel syndrome. Therefore, it is crucial to identify, early, the patients more prone to develop intestinal fibrosis to intensify follow-ups, switch to more aggressive treatments, and suggest lifestyle modifications. Scarce data are available concerning biomarkers and genetic determinants to predict which patient will develop intestinal fibrosis. Biologic or clinical markers would be useful to determine this subgroup of CD patients and to predict the onset of intestinal fibrosis and, ideally, its severity. Furthermore, the identification of environmental risk factors may suggest lifestyle changes aimed at modifying the natural course, thus decreasing the risk of complicated CD. In this review, we will critically revise clinical, environmental, genetic, and serologic factors that have been associated with a complicated CD course with a particular focus on the fibrostenosing phenotype and their possible implications as predictive factors of intestinal fibrosis.
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Affiliation(s)
- Riccardo Mager
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
| | - Giulia Roda
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy
| | - Mohammad Khaled Shalaby
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy
| | - Stefania Vetrano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
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Battistini C, Ballan R, Herkenhoff ME, Saad SMI, Sun J. Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases. Int J Mol Sci 2020; 22:E362. [PMID: 33396382 PMCID: PMC7795229 DOI: 10.3390/ijms22010362] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 12/26/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract (GIT), including Crohn's disease (CD) and ulcerative colitis (UC), which differ in the location and lesion extensions. Both diseases are associated with microbiota dysbiosis, with a reduced population of butyrate-producing species, abnormal inflammatory response, and micronutrient deficiency (e.g., vitamin D hypovitaminosis). Vitamin D (VitD) is involved in immune cell differentiation, gut microbiota modulation, gene transcription, and barrier integrity. Vitamin D receptor (VDR) regulates the biological actions of the active VitD (1α,25-dihydroxyvitamin D3), and is involved in the genetic, environmental, immune, and microbial aspects of IBD. VitD deficiency is correlated with disease activity and its administration targeting a concentration of 30 ng/mL may have the potential to reduce disease activity. Moreover, VDR regulates functions of T cells and Paneth cells and modulates release of antimicrobial peptides in gut microbiota-host interactions. Meanwhile, beneficial microbial metabolites, e.g., butyrate, upregulate the VDR signaling. In this review, we summarize the clinical progress and mechanism studies on VitD/VDR related to gut microbiota modulation in IBD. We also discuss epigenetics in IBD and the probiotic regulation of VDR. Furthermore, we discuss the existing challenges and future directions. There is a lack of well-designed clinical trials exploring the appropriate dose and the influence of gender, age, ethnicity, genetics, microbiome, and metabolic disorders in IBD subtypes. To move forward, we need well-designed therapeutic studies to examine whether enhanced vitamin D will restore functions of VDR and microbiome in inhibiting chronic inflammation.
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Affiliation(s)
- Carolina Battistini
- Department of Pharmaceutical and Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, Av. Lineu Prestes, 580, São Paulo, SP 05508-000, Brazil; (C.B.); (R.B.); (M.E.H.)
- Food Research Center, University of São Paulo, Rua do Lago, 250, São Paulo, SP 05508-080, Brazil
| | - Rafael Ballan
- Department of Pharmaceutical and Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, Av. Lineu Prestes, 580, São Paulo, SP 05508-000, Brazil; (C.B.); (R.B.); (M.E.H.)
- Food Research Center, University of São Paulo, Rua do Lago, 250, São Paulo, SP 05508-080, Brazil
| | - Marcos Edgar Herkenhoff
- Department of Pharmaceutical and Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, Av. Lineu Prestes, 580, São Paulo, SP 05508-000, Brazil; (C.B.); (R.B.); (M.E.H.)
- Food Research Center, University of São Paulo, Rua do Lago, 250, São Paulo, SP 05508-080, Brazil
| | - Susana Marta Isay Saad
- Department of Pharmaceutical and Biochemical Technology, School of Pharmaceutical Sciences, University of São Paulo, Av. Lineu Prestes, 580, São Paulo, SP 05508-000, Brazil; (C.B.); (R.B.); (M.E.H.)
- Food Research Center, University of São Paulo, Rua do Lago, 250, São Paulo, SP 05508-080, Brazil
| | - Jun Sun
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Microbiology and Immunology, UIC Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA
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Abstract
Innate lymphoid cells (ILCs) are a large family of cells of the immune system that performs various functions in immune defense, inflammation, and tissue remodeling. As a part of the innate immune system, ILCs are a distinct form of lymphocytes different from T and B cells. ILCs can provide host defense against the source of infection and initiate the repair and remodeling processes to restore and maintain host body homeostasis. The number of patients with Crohn’s disease (CD) worldwide has continued to increase in recent years and this disease has brought sickness and death to many families. Numerous studies have found that ILCs also undergo a series of alternations during the development of CD and contribute to this disease. Despite this, the pathogenesis of CD is still not fully explained. So, we keep researching and exploring. In this review, we have closely linked the latest progress on ILCs and CD, and introduced, in detail, the specific roles of four different types of ILCs in CD. We also describe new progress in the pathogenesis of CD, with particular emphasis on the plasticity of ILC3s in this disease. These new studies and findings may provide new insights and breakthrough points for the treatment of CD.
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Affiliation(s)
- Ying Wu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
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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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Asadzadeh-Aghdaei H, Mashayekhi K, Koushki K, Azimzadeh P, Rostami-Nejad M, Amani D, Chaleshi V, Haftcheshmeh SM, Sahebkar A, Zali MR. V617F-independent upregulation of JAK2 gene expression in patients with inflammatory bowel disease. J Cell Biochem 2019; 120:15746-15755. [PMID: 31069840 DOI: 10.1002/jcb.28844] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 01/12/2019] [Accepted: 01/25/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is one of the most important immune-mediated disorders of the gastrointestinal tract. Besides, IBD is associated with numerous extraintestinal complications such as venous thromboembolism (VTE), an important risk factor for vascular complications, which results in the increased morbidity and mortality. The JAK2 (Janus kinase 2) V617F mutation is a well-known point mutation which is involved in the pathogenesis of IBD, and VTE. Therefore, the aims of this study were to evaluate expression of JAK2 and association of V617F mutation in JAK2 of Iranian patients with IBD. METHODS Two hundred and forty-six patients with IBD (209 UC and 37 CD) and 206 healthy controls were enrolled in this study. The genomic DNA and total RNA were extracted from peripheral blood mononuclear cells (PBMCs). Then, the JAK2 V617F mutation detection was performed using the restriction fragment length polymorphism (RFLP) method. In addition, the JAK2 mRNA expression was evaluated using a quantitative polymerase chain reaction (q-PCR) using the SYBR Green assay. RESULTS There was no association of V61F mutation in patients with IBD with or without thrombosis compared with healthy control. However, the relative mRNA expression of JAK2 was significantly upregulated in patients with IBD in comparison with healthy control (P < 0.0001). In addition, the JAK2 mRNA expression was significantly decreased in patients with IBD having thrombosis compared with those without thrombosis ( P < 0.0001). CONCLUSIONS Taken together our findings suggested that JAK2 V61F-independent upregulation of JAK2 mRNA expression in patients with IBD. Moreover, despite the absence of JAK2 V617F mutation in patients with IBD, the increased gene expression of JAK2 can be explained by another molecular mechanism such as regulation of gene expression at the transcriptional level which may play crucial roles in the pathogenesis of IBD.
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Affiliation(s)
- Hamid Asadzadeh-Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kazem Mashayekhi
- Immuno-Biochemistry Lab, Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khadijeh Koushki
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pedram Azimzadeh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rostami-Nejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davar Amani
- Immunology Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Chaleshi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Mohammadian Haftcheshmeh
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Immunology, Nanotechnology Research Center, BuAli Research Institute, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Pike KA, Tremblay ML. Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease. Front Immunol 2018; 9:2504. [PMID: 30429852 PMCID: PMC6220082 DOI: 10.3389/fimmu.2018.02504] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 10/10/2018] [Indexed: 12/12/2022] Open
Abstract
Protein tyrosine phosphatases (PTPs) play a critical role in co-ordinating the signaling networks that maintain lymphocyte homeostasis and direct lymphocyte activation. By dephosphorylating tyrosine residues, PTPs have been shown to modulate enzyme activity and both mediate and disrupt protein-protein interactions. Through these molecular mechanisms, PTPs ultimately impact lymphocyte responses to environmental cues such as inflammatory cytokines and chemokines, as well as antigenic stimulation. Mouse models of acute and chronic intestinal inflammation have been shown to be exacerbated in the absence of PTPs such as PTPN2 and PTPN22. This increase in disease severity is due in part to hyper-activation of lymphocytes in the absence of PTP activity. In accordance, human PTPs have been linked to intestinal inflammation. Genome wide association studies (GWAS) identified several PTPs within risk loci for inflammatory bowel disease (IBD). Therapeutically targeting PTP substrates and their associated signaling pathways, such as those implicated in CD4+ T cell responses, has demonstrated clinical efficacy. The current review focuses on the role of PTPs in controlling CD4+ T cell activity in the intestinal mucosa and how disruption of PTP activity in CD4+ T cells can contribute to intestinal inflammation.
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Affiliation(s)
- Kelly A Pike
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada.,Inception Sciences Canada, Montréal, QC, Canada
| | - Michel L Tremblay
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada.,Rosalind and Morris Goodman Cancer Centre, McGill University, Montréal, QC, Canada.,Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, QC, Canada.,Department of Biochemistry, McGill University, Montréal, QC, Canada
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13
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Danese S, Furfaro F, Vetrano S. Targeting S1P in Inflammatory Bowel Disease: New Avenues for Modulating Intestinal Leukocyte Migration. J Crohns Colitis 2018; 12:S678-S686. [PMID: 28961752 DOI: 10.1093/ecco-jcc/jjx107] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Sphingosine 1 phosphate [S1P] is a bioactive lipid mediator involved in the regulation of several cellular processes though the activation of a G protein-coupled receptor family known as the S1P receptors [S1PRs]. Advances in the understanding of the biological activities mediated by S1PRs have sparked great interest in the S1P/S1PRs axes as new therapeutic targets for the modulation of several cellular processes. In particular, the S1P/S1PR1 axis has been identified as key regulator for lymphocyte migration from lymph nodes. The blockade of this axis is emerging as a new therapeutic approach to control the aberrant leukocyte migration into the mucosa in inflammatory bowel disease [IBD]. This review briefly summarises the current evidence coming from clinical studies, and discusses the future prospects of S1P inhibitors for treatment of inflammatory bowel disease.
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Affiliation(s)
- Silvio Danese
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
| | - Federica Furfaro
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Stefania Vetrano
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
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14
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Katsanos KH, Papadakis KA. Inflammatory Bowel Disease: Updates on Molecular Targets for Biologics. Gut Liver 2018; 11:455-463. [PMID: 28486793 PMCID: PMC5491079 DOI: 10.5009/gnl16308] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 08/03/2016] [Accepted: 08/03/2016] [Indexed: 12/13/2022] Open
Abstract
Therapy for inflammatory bowel disease (IBD) has changed, with several new agents being evaluated. The era of anti-tumor necrosis factor (anti-TNF) antibody therapy saw remarkable progress in IBD therapy. Some patients, however, do not respond to anti-TNF treatment, or their response decreases over time. This phenomenon highlights the need to identify new molecular targets for therapy in IBD. The targets of new therapeutic molecules in IBD must aim to restore immune dysregulation by the inhibition of proinflammatory cytokines (TNF-α, interleukin [IL]-6, IL-13, IL-17, IL-18, and IL-21) and augmentation of the effect of anti-inflammatory cytokines (IL-10, IL-11, and transforming growth factor β) and to pursue new anti-inflammatory targets, such as regulatory T-cell therapy, Smad7 antisense, Janus-activated kinase inhibition, Toll-like receptor stimulation, leukocyte adhesion, and blockade of T-cell homing via integrins and mucosal addressin cellular adhesion molecule-1. In addition, potential molecular targets could restore mucosal barrier function and stimulate mucosal healing. Despite these potential targets, the value and clinical significance of most new molecules remain unclear, and clinical efficacy and safety must be better defined before their implementation in clinical practice. This article aims to review the promising and emerging molecular targets that could be clinically meaningful for novel therapeutic approaches.
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Affiliation(s)
- Konstantinos H Katsanos
- Division of Gastroenterology, Department of Internal Medicine, University of Ioannina School of Health Sciences, Ioannina, Greece
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15
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SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCε-dependent Pathway. Inflamm Bowel Dis 2017; 23:1730-1740. [PMID: 28906292 DOI: 10.1097/mib.0000000000001250] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The integrity of the gut barrier in patients with inflammatory bowel disease is known to be impaired but the exact mechanisms remain mostly unknown. SHANK3 mutations are associated with autism, and patients with autism are known to have higher proportions of inflammatory bowel disease. Here, we explore the role of SHANK3 in inflammatory bowel disease, both in vivo and in vitro. METHODS Dextran sulfate sodium colitis was induced in SHANK3 knockout mice. Transepithelial electrical resistance, paracellular permeability, and Salmonella invasion assays were used to evaluate epithelial barrier function, in vitro and in vivo. Expression of tight junction proteins, protein kinases, and MAP kinase phosphorylation changes were analyzed by immunoblotting after overexpression or knockdown of SHANK3 expression. SHANK3 expression in intestinal tissue from patients with Crohn's disease was analyzed by quantitative polymerase chain reaction and immunohistochemistry. RESULTS SHANK3 knockout mice were more susceptible to dextran sulfate sodium. SHANK3 knockout resulted in a leaky epithelial barrier phenotype, as demonstrated by decreased transepithelial electrical resistance, increased paracellular permeability, and increased Salmonella invasion. Overexpression of SHANK3 enhanced ZO-1 expression, and knockdown of SHANK3 resulted in decreased expression of ZO-1. Regulation of ZO-1 expression by SHANK3 seems to be mediated through a PKCε-dependent pathway. SHANK3 expression correlated with ZO-1 and PKCε in colonic tissue of patients with Crohn's disease. CONCLUSIONS The expression level of SHANK3 affects ZO-1 expression and the barrier function in intestinal epithelial cells. This may provide novel insights in Crohn's disease pathogenesis and treatment.
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16
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Park JH, Peyrin-Biroulet L, Eisenhut M, Shin JI. IBD immunopathogenesis: A comprehensive review of inflammatory molecules. Autoimmun Rev 2017; 16:416-426. [PMID: 28212924 DOI: 10.1016/j.autrev.2017.02.013] [Citation(s) in RCA: 211] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 01/19/2017] [Indexed: 02/06/2023]
Abstract
Inflammatory molecules play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease, both of which are chronic inflammatory conditions of the gastrointestinal tract. Abnormal expressions of pro- and anti-inflammatory molecules have been described to cause an imbalance to the gut innate and adaptive immunity, and recently a large portion of research in IBD has been geared towards identifying novel molecules that may be used as potential therapeutic targets. Understanding of these inflammatory molecules has suggested that although ulcerative colitis and Crohn's disease share many common clinical symptoms and signs, they are in fact two separate clinical entities characterized by different immunopathogenesis. In this review, we comprehensively discuss the roles of numerous inflammatory molecules including but not limited to cytokines, chemokines, inflammasomes, microRNAs and neuropeptides and their expression status in ulcerative colitis and Crohn's disease in relation to their effects on the overall intestinal inflammatory process.
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Affiliation(s)
- Jae Hyon Park
- Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
| | - Laurent Peyrin-Biroulet
- Inserm U954 and Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, France
| | - Michael Eisenhut
- Department of Paediatrics, Luton & Dunstable University Hospital NHS Foundation Trust, Lewsey Road, Luton, LU40DZ, United Kingdom
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Republic of Korea.
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17
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Ma T, Wu S, Yan W, Xie R, Zhou C. A functional variant of ATG16L2 is associated with Crohn's disease in the Chinese population. Colorectal Dis 2016; 18:O420-O426. [PMID: 27611316 DOI: 10.1111/codi.13507] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 05/29/2016] [Indexed: 12/16/2022]
Abstract
AIM To determine whether genetic polymorphism of the ATG16L2 gene is functionally associated with the incidence of Crohn's disease (CD) in the Chinese population. METHOD The single nucleotide polymorphism (SNP) rs11235604 of the ATG16L2 gene was genotyped in 363 patients with CD and 486 healthy volunteers from the Chinese Han population. The distributions of the genotype and allele frequency were compared between patients and controls by the chi-square test. The mRNA expression of ATG16L2 in T cells was evaluated by real-time PCR. Comparisons of mRNA expression of ATG16L2 between patients and controls and between patients with genotype CC and genotype CT/TT were performed with the Student's t-test. RESULTS Compared with the controls, patients were found to have a significantly higher proportion of genotype TT (5.5% vs 2.5%, P = 0.04). Allele T was the risk allele for the disease (16.3% vs 12.3%, P = 0.02), with an odds ratio of 1.31 (95% CI 1.04-1.67). The ATG16L2 mRNA of the patients was significantly reduced when compared with the controls (0.0044 ± 0.0018 vs 0.0064 ± 0.0023, P < 0.001). Patients with genotype TT/CT had a significant lower level of ATG16L2 mRNA than patients with genotype CC (0.0036 ± 0.0016 vs 0.0053 ± 0.0028, P = 0.005). CONCLUSIONS ATG16L2 is a susceptibility gene for CD in the Chinese population. The rs11235604 SNP is remarkably associated with downregulation of the expression of ATG16L2. Further investigation into the gene's function is warranted for a comprehensive knowledge of the contribution of the variant to the development of CD.
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Affiliation(s)
- T Ma
- Department of Gastroenterology, Huai'an First People's Hospital of Nanjing Medical University, Huai'an, China
| | - S Wu
- Department of Gastroenterology, Huai'an First People's Hospital of Nanjing Medical University, Huai'an, China
| | - W Yan
- Department of Gastroenterology, Huai'an First People's Hospital of Nanjing Medical University, Huai'an, China
| | - R Xie
- Department of Gastroenterology, Huai'an First People's Hospital of Nanjing Medical University, Huai'an, China
| | - C Zhou
- Department of Gastroenterology, Huai'an First People's Hospital of Nanjing Medical University, Huai'an, China.
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18
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Hedl M, Proctor DD, Abraham C. JAK2 Disease-Risk Variants Are Gain of Function and JAK Signaling Threshold Determines Innate Receptor-Induced Proinflammatory Cytokine Secretion in Macrophages. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2016; 197:3695-3704. [PMID: 27664279 PMCID: PMC5127452 DOI: 10.4049/jimmunol.1600845] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 08/24/2016] [Indexed: 12/12/2022]
Abstract
JAK2 genetic variants are associated with inflammatory bowel disease (IBD) and JAK inhibitors are being evaluated for therapy targeting immune-mediated diseases, including IBD. As JAK pathway-mediated cytokine regulation varies across cell types and stimulation conditions, we examined how JAK signaling and IBD-associated JAK2 variants regulate distinct acute and chronic microbial product exposure outcomes in human myeloid cells, consistent with the conditions of initial entry and ongoing intestinal tissue residence, respectively. Macrophages from controls and ulcerative colitis patients carrying the IBD-risk rs10758669 CC genotype showed increased JAK2 expression and nucleotide-binding oligomerization domain 2-induced JAK2 phosphorylation relative to AA carriers. Interestingly, the threshold of JAK2 expression and signaling determined pattern-recognition receptor (PRR)-induced outcomes; whereas anti-inflammatory cytokines progressively decreased with lower JAK2 expression, proinflammatory cytokines switched from decreased to increased secretion below a certain JAK2 expression threshold. Low JAK2-expressing rs10758669 AA macrophages were above this threshold; consequently, both PRR-induced pro- and anti-inflammatory cytokines were decreased. However, relative to rs10758669 CC risk carriers, AA carrier macrophages switched to increased nucleotide-binding oligomerization domain 2-induced proinflammatory cytokines at lower therapeutically used JAK inhibitor doses. Importantly, JAK inhibitors increased proinflammatory cytokines secreted by peripheral macrophages following chronic PRR stimulation and by human intestinal myeloid cells following exposure to intestinal pathogens. Mechanistically, the decreased response to and secretion of autocrine/paracrine IL-10, IL-4, IL-22 and thymic stromal lymphopoietin regulated these JAK-dependent outcomes in myeloid cells. Taken together, the JAK signaling threshold determines whether PRR-induced pro- and anti-inflammatory cytokines are reciprocally regulated in myeloid cells; consideration of JAK2 genotype and targeting of specific cell types might improve JAK-targeted therapy in immune-mediated diseases.
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Affiliation(s)
- Matija Hedl
- Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT 06520
| | - Deborah D Proctor
- Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT 06520
| | - Clara Abraham
- Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT 06520
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19
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A Promoter Variant Within the Aryl Hydrocarbon Receptor Gene Is Associated with an Epithelial Barrier Defect in Smokers with Crohn's Disease. Inflamm Bowel Dis 2016; 22:2356-68. [PMID: 27598741 DOI: 10.1097/mib.0000000000000910] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Smoking worsens Crohn's disease (CD). The aryl hydrocarbon receptor (AhR) is a transcription factor that mediates the toxicity of dioxinlike chemicals. We hypothesized that AHR variants and smoking influence CD. METHODS Exon-intron boundaries and coding and promoter regions of AHR gene were sequenced (28 patients with inflammatory bowel disease; 4 healthy controls). Two identified variants (rs7796976 and rs2066853) were studied for an association with intestinal permeability (IP, oral sugar test) in patients with inflammatory bowel disease (stratified according to the smoking status). AHR expression was analyzed by quantitative real-time polymerase chain reaction in colonic biopsies from patients with CD (n = 53). Case-control analysis including a genotype-phenotype correlation was performed for both variants (n = 767 patients with inflammatory bowel disease; n = 466 healthy controls). RESULTS Sequencing identified a putative promoter variant (rs7796976) and a nonsynonymous variant (rs2066853; Arg554Lys) in AHR, both predicted to be functionally relevant. The major G-allele of rs7796976 increased the risk for disturbed IP (odds ratio 1.9, 95% confidence interval [CI], 1.1-3.2) in CD but not ulcerative colitis. We observed an additive effect of the rs7796976 genotype and smoking on IP (P = 0.005), which was also shown for rs2066853 (P = 0.004; variants not linked). Both variants showed a genotype-dependent AHR expression in colonic biopsies of patients with CD. No overall association with either CD or ulcerative colitis was observed; however, the rs7796976 genotype and smoking increased the risk for the L4 phenotype in CD. CONCLUSION Smoking and functionally relevant AHR variants increase IP in CD. Because AhR is known to mediate between smoking and inflammation, these variants might be involved in the deleterious effect of smoking on CD.
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20
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Fu L, Wei LW, Zhao MD, Zhu JL, Chen SY, Jia XB, Lai SJ. Investigation of JAKs/STAT-3 in lipopolysaccharide-induced intestinal epithelial cells. Clin Exp Immunol 2016; 186:75-85. [PMID: 27357529 DOI: 10.1111/cei.12835] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/13/2016] [Accepted: 06/27/2016] [Indexed: 12/30/2022] Open
Abstract
Janus-activated kinase (JAKs)-signal transducer and activator of transcription 3 (STAT-3) signalling play critical roles in immunoregulation and immunopathology, which involve inflammatory responses and enteritis. JAK phosphorylates STAT-3 in response to stimulation by cytokines or growth factors, and then activates or represses the gene expression. STAT-3 is activated persistently in cancer cells and contributes to the malignant progression of various types of cancer and inflammation. To elucidate the different roles of JAKs in the activation of STAT-3, the lipopolysaccharide-induced primary intestinal epithelial cell (IEC) acute inflammatory model was established. Small interference RNAs (siRNAs) were then employed to attenuate the expression levels of JAKs. Real-time quantitative reverse transcription-polymerase chain reaction (PCR) (qRT-PCR) revealed that JAK mRNA levels were reduced efficiently by JAK-specific siRNAs. Under the IEC inflammatory model transfected with si-JAK, which equates to effective silencing, qRT-PCR and Western blot assays, suggested that knockdowns of JAK attenuated the JAK-induced down-regulation of STAT-3 at the mRNA or protein levels. In particular, JAK1 played a key role, which was consistent with the RNA-Seq results. Subsequently, the expression levels of proinflammatory cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α were down-regulated in the IEC inflammatory model transfected with si-JAK1. JAK1 appears as a direct activator for STAT-3, whereas treatments targeting JAK1 repressed STAT-3 sufficiently pathways in the IEC inflammatory model. Therefore, the control of JAK1 using siRNAs has the potential to be an effective strategy against enteritis.
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Affiliation(s)
- L Fu
- Laboratory Animal Center, Southwest Medical University, Luzhou, China
| | - L-W Wei
- Laboratory Animal Center, Southwest Medical University, Luzhou, China
| | - M-D Zhao
- Laboratory Animal Center, Southwest Medical University, Luzhou, China
| | - J-L Zhu
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, China
| | - S-Y Chen
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, China
| | - X-B Jia
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, China
| | - S-J Lai
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, China
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21
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Verstockt B, Cleynen I. Genetic Influences on the Development of Fibrosis in Crohn's Disease. Front Med (Lausanne) 2016; 3:24. [PMID: 27303667 PMCID: PMC4885006 DOI: 10.3389/fmed.2016.00024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 05/13/2016] [Indexed: 12/11/2022] Open
Abstract
Fibrostenotic strictures are an important complication in patients with Crohn’s disease (CD), very often necessitating surgery. This fibrotic process develops in a genetically susceptible individual and is influenced by an interplay with environmental, immunological, and disease-related factors. A deeper understanding of the genetic factors driving this fibrostenotic process might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapy. Here, we review the genetic factors that have been associated with the development of fibrosis in patients with CD, as well as their potential pathophysiological mechanism(s). We also hypothesize on clinical implications, if any, and future research directions.
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Affiliation(s)
- Bram Verstockt
- Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK; Translational Research in Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Isabelle Cleynen
- Laboratory of Complex Genetics, Department of Human Genetics, KU Leuven , Leuven , Belgium
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Abstract
IBD is a chronic inflammatory condition of the gastrointestinal tract encompassing two main clinical entities: Crohn's disease and ulcerative colitis. Although Crohn's disease and ulcerative colitis have historically been studied together because they share common features (such as symptoms, structural damage and therapy), it is now clear that they represent two distinct pathophysiological entities. Both Crohn's disease and ulcerative colitis are associated with multiple pathogenic factors including environmental changes, an array of susceptibility gene variants, a qualitatively and quantitatively abnormal gut microbiota and a broadly dysregulated immune response. In spite of this realization and the identification of seemingly pertinent environmental, genetic, microbial and immune factors, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. An important reason for this unsatisfactory situation is the currently limited comprehension of what are the truly relevant components of IBD immunopathogenesis. This article will comprehensively review current knowledge of the classic immune components and will expand the concept of IBD immunopathogenesis to include various cells, mediators and pathways that have not been traditionally associated with disease mechanisms, but that profoundly affect the overall intestinal inflammatory process.
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Affiliation(s)
- Heitor S P de Souza
- Department of Gastroenterology &Multidisciplinary Research Laboratory, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
| | - Claudio Fiocchi
- Department of Pathobiology, Lerner Research Institute, Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
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Prager M, Buettner J, Buening C. Genes involved in the regulation of intestinal permeability and their role in ulcerative colitis. J Dig Dis 2015; 16:713-22. [PMID: 26512799 DOI: 10.1111/1751-2980.12296] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 10/14/2015] [Accepted: 10/26/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Genome-wide association studies have identified single nucleotide polymorphisms in genes that might influence intestinal barrier function (HNF4A, ECM1, CDH1 and LAMB1) to increase the risk for ulcerative colitis (UC). The aim of our study was to detect causative sequence alterations and provide a functional link to a disturbed intestinal permeability (IP) in UC. METHODS A total of 19 UC patients with increased IP (lactulose/mannitol ratio measured by sugar drink test) were identified from a large database, and exon/intron boundaries, coding and promoter regions of HNF4A, ECM1, CDH1 and LAMB1 were sequenced. Variants with putative protein alterations were studied for an association with IP in 82 UC patients. A case-control analysis including a genotype phenotype correlation was performed in 743 patients with inflammatory bowel disease (IBD) and 473 healthy controls. RESULTS In UC patients, we identified 11 missense-mutations, 12 synonymous mutations, one putative promoter variant and three variants in introns close to the intron/exon boundaries (CDH1, HNF4A). For several variants prediction tools revealed damaging protein alterations. None of the studied variants, however, showed an association with an increased IP in UC. In the case-control analysis, the frequency of all investigated variants did not differ between UC or Crohn's disease and healthy controls. Furthermore, no significant association was found to a distinct phenotype. CONCLUSIONS Despite our large sequencing approach, we could not identify protein altering variants in the genes HNF4A, ECM1, CDH1 and LAMB1 which could explain an impaired intestinal barrier function in UC. The functional relevance of these genes in IBD remains unknown.
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Affiliation(s)
- Matthias Prager
- Department of Hepatology and Gastroenterology, Charité, Universitätsmedizin Berlin, Campus Mitte
| | - Janine Buettner
- Department of Hepatology and Gastroenterology, Charité, Universitätsmedizin Berlin, Campus Mitte
| | - Carsten Buening
- Department of Hepatology and Gastroenterology, Charité, Universitätsmedizin Berlin, Campus Mitte.,Krankenhaus Waldfriede, Department of Internal Medicine, Berlin, Germany
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24
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Zhang JX, Song J, Wang J, Dong WG. JAK2 rs10758669 polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a meta-analysis. Inflammation 2015; 37:793-800. [PMID: 24385239 DOI: 10.1007/s10753-013-9798-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In this meta-analysis, we aimed to clarify the impact of Janus kinase 2 (JAK2) rs10758669 polymorphisms on ulcerative colitis (UC) and Crohn's disease (CD) risk. Data were extracted, and pooled odd ratios (ORs) as well as 95% confidence intervals (95%CIs) were calculated. Eleven studies with 7009 CD patients, 7929 UC patients, and 19235 controls were included. The results showed that JAK2 rs10758669 polymorphism was associated with CD (AC vs. AA, OR = 1.16, 95%CI, 1.08-1.24; CC vs. AA, OR = 1.29, 95%CI, 1.17-1.43; AC + CC vs. AA, OR = 1.19, 95%CI, 1.11-1.27; CC vs. AA + AC, OR = 1.19, 95%CI, 1.09-1.31; C vs. A, OR = 1.14, 95%CI, 1.09-1.20) and UC susceptibility (AC vs. AA, OR = 1.14, 95%CI, 1.06-1.22; CC vs. AA, OR = 1.33, 95%CI, 1.20-1.47; AC + CC vs. AA, OR = 1.18, 95%CI, 1.10-1.27; CC vs. AA + AC, OR = 1.24, 95%CI, 1.12-1.36; C vs. A, OR = 1.15, 95%CI, 1.10-1.21). But no significant association was found between JAK2 rs10758669 polymorphism with CD in Asian. Either in adult-onset group or multi-age group, hospital-based group or population-based group, JAK2 rs10758669 polymorphism was associated with CD and UC susceptibility. This meta-analysis indicated that JAK2 rs10758669 polymorphism was a risk factor both for CD and UC, especially in Caucasian. The differences in age of onset and study design did not influence the associations obviously. Gene-gene and gene-environment interactions should be investigated in the future.
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Affiliation(s)
- Ji-Xiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
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25
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Zhang J, Chen J, Gu J, Guo H, Chen W. Association of IL23R and ATG16L1 with susceptibility of Crohn's disease in Chinese population. Scand J Gastroenterol 2014; 49:1201-6. [PMID: 25048429 DOI: 10.3109/00365521.2014.936031] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES To investigate whether gene polymorphisms of ATG16L1 and IL23R are associated with the susceptibility of Crohn's disease (CD) in Chinese population. METHODS A total of 420 patients with CD and 450 age- and sex-matched healthy volunteers from Chinese Han population were included in this study. Single nucleotide polymorphisms (SNPs) rs2241880 of ATG16L1 and rs11209026, rs1004819, and rs1495965 of IL23R were genotyped. The differences of genotype and allele distributions between CD patients and healthy controls were assessed using the Chi-squared test. Besides, subgroup analysis of disease groups was performed using the Chi-squared test. RESULTS For ATG16L1, patients were found to have significantly higher proportion of genotype GG (18.3%), when compared with the normal controls (12.4%). Allele G was found to be the risk allele for the disease (34.3% vs. 29.0%, p = 0.016) with an odds ratio of 1.18. For IL23R, all three SNPs were found not to be associated with the development of CD. None of these four SNPs was found to be associated with the clinical features of the patients, including age at diagnosis, disease location, and behavior. CONCLUSION The original genome-wide association studies finding on ATG16L1 gene should be robust and this gene does play a role in the pathogenesis of CD in the Chinese population. However, the role of IL23R gene in the occurrence of CD remains obscure.
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Affiliation(s)
- Jie Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Soochow University , Suzhou , China
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Prager M, Durmus T, Büttner J, Molnar T, de Jong DJ, Drenth JP, Baumgart DC, Sturm A, Farkas K, Witt H, Büning C. Myosin IXb variants and their pivotal role in maintaining the intestinal barrier: a study in Crohn's disease. Scand J Gastroenterol 2014; 49:1191-200. [PMID: 25098938 DOI: 10.3109/00365521.2014.928903] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Myosin IXb (MYO9B) is involved in the regulation of epithelial barrier function. We hypothesized that MYO9B variants are associated with increased intestinal permeability measured in patients with Crohn's disease (CD), where barrier dysfunction is crucially involved in disease development. METHODS We sequenced MYO9B and genotyped five MYO9B variants (rs1545620, rs1457092, rs2279003, rs2305764 and rs2279002) and correlated these data to measurement of intestinal permeability in German CD patients (n = 122) obtained by standard oral sugar test using the lactulose/mannitol ratio after measurement of urinary excretion. We furthermore studied MYO9B variants in three European cohorts with inflammatory bowel disease (IBD) and healthy controls : Germany (CD = 264; ulcerative colitis = 143 [UC]; HC = 372); Hungary (CD = 147; UC = 117; HC = 195), the Netherlands (CD = 157; HC = 219). RESULTS We found an association for four studied MYO9B variants to an increased intestinal permeability in CD patients (rs1545620, p = 0.010; rs1457092, p = 0.024; rs2279003, p = 0.003; rs2305764, p = 0.015). Furthermore, we observed significantly higher absolute values of intestinal permeability for individuals carrying risk alleles within MYO9B. Looking for an overall disease association, only the rs2305764 variant was associated with CD in the Dutch cohort (p = 0.004), but not in the German or Hungarian cohort. No association to UC or a distinct phenotype in both CD and UC patients was observed for all studied MYO9B variants. CONCLUSION Our data suggest a link between MYO9B variants to an increased intestinal permeability in CD patients. This supports the influence of Myosin IXb on the integrity of the epithelial barrier. The role of MYO9B variants in the overall susceptibility to IBD, however, remains to be elucidated.
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Affiliation(s)
- Matthias Prager
- Department of Gastroenterology and Hepatology, Charité, Campus Mitte, Universitätsmedizin Berlin , Berlin , Germany
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Genetic effects of single nucleotide polymorphisms in JAK2 and STAT5A genes on susceptibility of Chinese Holsteins to mastitis. Mol Biol Rep 2014; 41:8293-301. [PMID: 25205126 DOI: 10.1007/s11033-014-3730-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 09/03/2014] [Indexed: 02/06/2023]
Abstract
The JAK-STAT pathway plays a key role in host immunity. The present study was designed to evaluate the effects of single nucleotide polymorphisms (SNPs) in STAT5A and JAK2 genes on some serum cytokines, mastitis and milk production traits. Two SNPs (SNP1 43046497A/C and SNP2 43047829G/A) in STAT5A, and four SNPs in JAK2 (SNP3 39652267A/G, SNP4 39630048C/T, SNP5 39631044G/A, and SNP6 39631175T/C) were revealed and genotyped in 268 Chinese Holstein cattle. Fixed model was used to analyze the association of SNPs with phenotypes by general linear model procedure of SAS 9.1. SNP1 and SNP4 were significantly associated with IL-6 and IL-17 (P < 0.05), respectively. In JAK2 gene, SNP3 was highly significant (P < 0.01) and SNP5 was significant (P < 0.05) in association with SCC, whereas, the association of SNP6 was found significant (P < 0.05) with both SCC and SCS. Combination genotype analysis revealed that SNPs in JAK2 gene significantly associated with SCC and SCS were associated significantly with the corresponding phenotypes in combinations as well. The GG genotype of SNP3 individually and in any combination genotypes showed lowest SCC. The dominant effect of SNP1, SNP5 and SNP6 was found highly significant (P < 0.01) on the corresponding phenotypes (IL-6, SCC and SCS). As for haplotype analysis, two haplotypes were revealed between the two SNPs of STAT5A gene and four haplotypes amongst four SNPs in JAK2 gene; strong linkage disequilibrium (D' > 0.9) was observed between all these haplotypes. The results imply that the identified SNPs could be powerful markers to select dairy cattle with improved genetic resistance against mastitis.
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Dave M, Papadakis KA, Faubion WA. Immunology of inflammatory bowel disease and molecular targets for biologics. Gastroenterol Clin North Am 2014; 43:405-24. [PMID: 25110250 PMCID: PMC4480636 DOI: 10.1016/j.gtc.2014.05.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Inflammatory bowel disease (IBD) is an immune-mediated disease and involves a complex interplay of host genetics and environmental influences. Recent advances in the field, including data from genome-wide association studies and microbiome analysis, have started to unravel the complex interaction between host genetics and environmental influences in the pathogenesis of IBD. A drawback of current clinical trials is inadequate or lack of immune phenotyping of patients. However, recent advances in high-throughput technologies provide an opportunity to monitor the dynamic and complex immune system, which may to lead to a more personalized treatment approach in IBD.
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Suratanee A, Plaimas K. Identification of inflammatory bowel disease-related proteins using a reverse k-nearest neighbor search. J Bioinform Comput Biol 2014; 12:1450017. [DOI: 10.1142/s0219720014500176] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic disease whose incidence and prevalence increase every year; however, the pathogenesis of IBD is still unclear. Thus, identifying IBD-related proteins is important for understanding its complex disease mechanism. Here, we propose a new and simple network-based approach using a reverse k-nearest neighbor ( R k NN ) search to identify novel IBD-related proteins. Protein–protein interactions (PPI) and Genome-Wide Association Studies (GWAS) were used in this study. After constructing the PPI network, the R k NN search was applied to all of the proteins to identify sets of influenced proteins among their k-nearest neighbors ( R k NNs ). An observed protein whose influenced proteins were mostly known IBD-related proteins was statistically identified as a novel IBD-related protein. Our method outperformed a random aspect, k NN search, and centrality measures based on the network topology. A total of 39 proteins were identified as IBD-related proteins. Of these proteins, 71% were reported at least once in the literature as related to IBD. Additionally, these proteins were found over-represented in the IBD pathway and enriched in importantly functional pathways in IBD. In conclusion, the R k NN search with the statistical enrichment test is a great tool to identify IBD-related proteins to better understand its complex disease mechanism.
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Affiliation(s)
- Apichat Suratanee
- Department of Mathematics, Faculty of Applied Science, King Mongkut's University of Technology North Bangkok, 1518 Pracharat 1 Road, Wongsawang, Bangsue, Bangkok 10800, Thailand
| | - Kitiporn Plaimas
- Integrative Bioinformatics and Systems Biology Group, Advanced Virtual and Intelligent Computing Research Center (AVIC), Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Phyathai Road, Patumwan, Bangkok 10330, Thailand
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Lu Y, Li CY, Lin SS, Yuan P. IRGM rs13361189 polymorphism may contribute to susceptibility to Crohn's disease: A meta-analysis. Exp Ther Med 2014; 8:607-613. [PMID: 25009628 PMCID: PMC4079410 DOI: 10.3892/etm.2014.1736] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 04/10/2014] [Indexed: 01/11/2023] Open
Abstract
The aim of the present meta-analysis was to evaluate the correlation between a common polymorphism, rs13361189 C>T in the immunity-related GTPase M (IRGM) gene, and susceptibility to Crohn's disease (CD). The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library and CBM databases were investigated from database inception through to October 1, 2013 without the application of any language restrictions. The meta-analysis was performed using STATA 12.0 software and the relative risk (RR) with a 95% confidence interval (CI) was calculated. Seven case-control studies were included with a total of 3,093 CD patients and 3,227 healthy control subjects. The results of the meta-analysis revealed that the IRGM rs13361189 polymorphism correlates with an increased risk of CD (T allele versus C allele: RR=1.25 with 95% CI, 1.04-1.50; P=0.016 and CT + TT versus CC: RR=1.21 with 95% CI, 1.03-1.42; P=0.018). A subgroup analysis conducted using a genotyping method indicated that the IRGM rs13361189 polymorphism was correlated with an increased risk of CD in the TaqMan® (T allele versus C allele: RR=1.32 with 95% CI, 1.01-1.73; P=0.042) and the polymerase chain reaction-restriction fragment length polymorphism subgroups (T allele versus C allele: RR=1.80 with 95% CI, 1.32-2.45; P<0.001 and CT + TT versus CC: RR=1.61 with 95% CI, 1.19-2.18; P=0.018). However, no correlation was observed in the direct sequencing subgroup (P>0.05). Further subgroup analysis by sample size demonstrated significant correlations between the IRGM rs13361189 polymorphism and an increased risk of CD in the large sample-size subgroup (T allele versus C allele: RR=1.46 with 95% CI, 1.26-1.68; P<0.001 and CT + TT versus CC: RR=1.40 with 95% CI, 1.21-1.62; P<0.001). However, no correlation was identified between the IRGM rs13361189 polymorphism and CD risk in the small sample-size subgroup (P>0.05). The present meta-analysis indicated that the IRGM rs13361189 polymorphism may contribute to susceptibility to CD. Thus, IRGM rs13361189 polymorphism may be a potential biomarker for the early diagnosis of CD.
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Affiliation(s)
- Yao Lu
- Department of Anorectal, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Chun-Yu Li
- Department of Anorectal, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Shu-Sen Lin
- Department of Anorectal, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Peng Yuan
- Department of Anorectal, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
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rs744166 polymorphism of the STAT3 gene is associated with risk of gastric cancer in a Chinese population. BIOMED RESEARCH INTERNATIONAL 2014; 2014:527918. [PMID: 24864251 PMCID: PMC4017712 DOI: 10.1155/2014/527918] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 04/01/2014] [Indexed: 12/11/2022]
Abstract
The aim of this study was to explore the association between polymorphisms in signal transducer and activator of transcription protein 3 (STAT3) and the risk of gastric cancer. In the present study, a case-control study was conducted in which rs2293152 and rs744166 polymorphisms in STAT3 were analyzed in 209 Chinese patients with gastric cancer and 294 cancer-free controls. The genotypes were determined by polymerase chain reaction restriction fragment length polymorphism method. For the rs744166 polymorphism, the TC genotype (adjusted OR = 0.60, 95% CI = 0.39-0.92, and P = 0.020) and CC genotype (adjusted OR = 0.41, 95% CI = 0.21-0.80, and P = 0.009) were associated with a decreased risk of gastric cancer compared to the TT genotype. However, rs2293152 did not show any difference in gastric cancer risk between patients and controls in the CG/CC genotype compared to the GG genotype. Besides, the SNP effects were additive to the effects of environmental factors without any interaction between them in the susceptibility to gastric cancer. Collectively, rs744166 polymorphism might be significantly associated with a decreased risk of gastric cancer in a Chinese population. Additionally, polymorphisms in STAT3, along with environmental factors, might be associated with the development of gastric cancer.
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Lu XC, Tao Y, Wu C, Zhao PL, Li K, Zheng JY, Li LX. Association between variants of the autophagy related gene--IRGM and susceptibility to Crohn's disease and ulcerative colitis: a meta-analysis. PLoS One 2013; 8:e80602. [PMID: 24232856 PMCID: PMC3827440 DOI: 10.1371/journal.pone.0080602] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2013] [Accepted: 10/04/2013] [Indexed: 01/17/2023] Open
Abstract
Background Polymorphisms in immunity-related GTPase family M (IRGM) gene may be associated with inflammatory bowel disease (IBD) by affecting autophagy. However, the genetic association studies on three common variants in IRGM gene (rs13361189, rs4958847 and rs10065172) have shown inconsistent results. Methodology/ Principal Findings The PubMed and Embase were searched up to June 5, 2013 for studies on the association between three IRGM polymorphisms and IBD risk. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Finally, we performed a meta-analysis of 25 eligible studies in 3 SNPs located at IRGM gene by using a total of 20590 IBD cases and 27670 controls. The analysis showed modest significant association for the rs13361189, rs4958847 and rs10065172 variants in Crohn’s disease (CD): the risk estimates for the allele contrast were OR=1.306 (1.200-1.420), p=5.2×10-10, OR=1.182 (1.082-1.290), p=0.0002, and OR=1.248 (1.057-1.473), p=0.009 respectively (still significant when the p value was Bonferroni adjusted to 0.017). When stratified by ethnicity, significantly increased CD risk was observed in Europeans, but not in Asians. Conversely, there was no association of rs13361189 or rs4958847 variant with risk of ulcerative colitis (UC). Conclusions/ Significance These results indicated that autophagy gene-IRGM polymorphisms appear to confer susceptibility to CD but not UC, especially in Europeans. Our data may provide further understanding of the role of autophagy in the pathogenesis of CD.
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Affiliation(s)
- Xiao Cheng Lu
- Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Cleynen I, González JR, Figueroa C, Franke A, McGovern D, Bortlík M, Crusius BJA, Vecchi M, Artieda M, Szczypiorska M, Bethge J, Arteta D, Ayala E, Danese S, van Hogezand RA, Panés J, Peña SA, Lukas M, Jewell DP, Schreiber S, Vermeire S, Sans M. Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project. Gut 2013; 62:1556-65. [PMID: 23263249 DOI: 10.1136/gutjnl-2011-300777] [Citation(s) in RCA: 211] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. DESIGN This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. RESULTS Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02 × 10(-06), OR=1.90), stenosing (p=3.16 × 10(-06), OR=1.82) and penetrating (p=1.26 × 10(-02), OR=1.25) CD behaviours, and need for surgery (p=2.28 × e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86 × 10(-06), OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48 × 10(-06), OR=0.35) and surgical rate (p=1.71 × 10(-07), OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12 × 10(-03), HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01 × 10(-02), HR=1.29) among patients with low and high score. CONCLUSIONS This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.
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Affiliation(s)
- Isabelle Cleynen
- Department of Clinical and Experimental Medicine, KU Leuven, , Leuven, Belgium
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Association of single-nucleotide polymorphisms in the STAT3 gene with autoimmune thyroid disease in Chinese individuals. Funct Integr Genomics 2013; 13:455-61. [PMID: 24081513 PMCID: PMC3824579 DOI: 10.1007/s10142-013-0337-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Revised: 08/19/2013] [Accepted: 09/10/2013] [Indexed: 01/05/2023]
Abstract
The aim of this study was to investigate the association between signal transducer and activator of transcription 3 (STAT3) polymorphisms and autoimmune thyroid diseases and clinical features. We genotyped six single-nucleotide polymorphisms (SNPs) rs1053005, rs2293152, rs744166, rs17593222, rs2291281, and rs2291282 of STAT3 gene in 667 patients with autoimmune thyroid disease (417 Graves’ disease (GD) and 250 Hashimoto’s thyroiditis (HT)) and 301 healthy controls. The allele A from rs1053005 was significantly less frequent in both GD and HT patients (P = 0.0024, OR = 0.6958, 95%CI = 0.5508–0.8788; P = 0.0091, OR = 0.7013, 95%CI = 0.5397–0.9112, respectively). The AA genotype of rs1053005 was less in GD and HT patients too (P = 0.0025,OR = 0.6278, 95%CI = 0.466–0.847) and (P = 0.0036,OR = 0.601, 95%CI = 0.428–0.843). The allele G from rs17593222 increased the susceptibility to the ophthalmopathy development both in autoimmune thyroid disease (AITD) and GD patients (P = 0.0007, OR = 3.980, 95%CI = 1.871–8.464; P = 0.0081, OR = 3.378, 95%CI = 1.441–7.919, respectively). The allele A and AA genotype of SNP rs1053005 may protect individuals from the susceptibility to AITD and their frequency decreased in AITD patients. In addition, the allele G of rs17593222 may increase the ophthalmopathy risk in AITD patients. Our findings suggest the existence of association between STAT3 gene and AITD, thus adding STAT3 gene to the list of the predisposing genes to AITD.
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Michail S, Bultron G, Depaolo RW. Genetic variants associated with Crohn's disease. APPLICATION OF CLINICAL GENETICS 2013; 6:25-32. [PMID: 23935379 PMCID: PMC3735034 DOI: 10.2147/tacg.s33966] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Crohn’s disease is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can occur in any area throughout the digestive tract. This life-long disease commonly presents with abdominal pain, diarrhea, vomiting, and weight loss. While the exact etiology of this disease is largely unknown, it is thought to arise from an interaction between microbial, immunological, and environmental factors in a genetically susceptible host, whereby the immune system attacks the intestine as it cross reacts against gut microbial antigens. The study of genetic variants associated with Crohn’s disease has shed light on our understanding of disease pathophysiology. A large number of genetic variants identified in Crohn’s disease are related to genes targeting microbial recognition and bacterial wall sensing, the most common being NOD2/CARD15 gene. This review will discuss the recent advance in our knowledge of genetic variants of this disease and how they influence the disease course and prognosis.
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Affiliation(s)
- Sonia Michail
- The University of Southern California, Children's Hospital of Los Angeles, Los Angeles, CA, USA
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Yang L, Liu D, Liang S, Guo R, Zhang Z, Xu H, Yang C, Zhu Y. Janus kinase 2 polymorphisms are associated with risk in patients with gastric cancer in a Chinese population. PLoS One 2013; 8:e64628. [PMID: 23717640 PMCID: PMC3663844 DOI: 10.1371/journal.pone.0064628] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2012] [Accepted: 04/17/2013] [Indexed: 12/16/2022] Open
Abstract
AIM To evaluate the impact of the Janus kinase 2 single nucleotide polymorphisms (SNPs) on gastric cancer risk. METHODS In this hospital-based, case-control study, the genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism protocols in 661 individuals (359 gastric cancer patients and 302 age and sex matched cancer-free controls). RESULTS Both the frequency of A allele in rs2230724 and G allele in rs1887427 were more frequent in patients with gastric cancer (P = 0.013 and 0.001, respectively). Compared with the common genotype, subjects with the (AG+AA) genotypes of rs2230724 and the (AG+GG) genotypes of rs1887427 had a 59% and 98% increased risk of developing gastric cancer, respectively (P = 0.010, adjusted OR = 1.59, 95% CI = 1.12-2.27; P<0.001, adjusted OR = 1.98, 95% CI = 1.39-2.81, respectively). Further stratified analysis showed that the association between the risk of gastric cancer and the rare genotypes of rs2230724 were more profound in the subgroups of elder individuals (>56 years), males, nonsmokers and urban subjects, while the association between the risk and the rare genotypes of rs1887427 persisted in subgroups of younger individuals (≤56 years), males, nonsmokers and both of rural and urban subjects. CONCLUSION The JAK2 gene rs2230724 and rs1887427 polymorphisms are associated with an increased risk of gastric cancer in a Chinese Han population.
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Affiliation(s)
- Li Yang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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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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