The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type ii mice

Ando, Yumiko; Yang, Guo Xiang; Tsuda, Masanobu; Kawata, Kazuhito; Zhang, Weici; Nakajima, Takahiko; Tsuneyama, Koichi; Leung, Patrick S.C.; Lian, Zhe Xiong; Okazaki, Kazuichi; Ridgway, William M.; Norman, Gary L.; Ansari, Aftab A.; He, Xiaosong; Coppel, Ross L.; Gershwin, M. Eric

doi:10.1002/hep.25803

Cited by 39 publications

(38 citation statements)

References 35 publications

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“…We note that we have also taken advantage of our two well-developed animal models of PBC, 2OA-BSA immunized mice and the dnTGF-βRII mice, to examine the pathogenic role of IL-23/Th17 pathway. Although we demonstrated that 2OA-BSA immunization induced portal inflammation and bile duct damage were ameliorated in IL-23p19 −/− and IL-17 −/− mice compared with controls (22), the protective effects of IL-23p19/IL-17 deletion were absent in our dnTGF-βRII murine model (26). However, deletion of cytokines that are associated closely with Th17 cells, including IL-23p40, IL23-p19, IL-17, and IL-6, led to significantly lower serum titer of anti-nuclear antibodies, i.e.…”

Section: Discussionmentioning

confidence: 61%

IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy

et al. 2014

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The interleukin (IL)-12/IL-23 mediated Th1/Th17 signaling pathway has been associated with the etiopathogenesis of primary biliary cirrhosis (PBC). To address the cytokine microenvironment specifically in the liver, we examined the localized expression of cytokine subunits and their corresponding receptors using previously optimized immunohistochemistry with an extensive panel of antibodies directed at IL-12p70, IL-12p35, IFN-γ, IL-12RB2, IL-23p40, IL-23p19, IL-17 and IL-23R using liver from PBC (n=51) and non-PBC (n=80) control liver disease patients. Multiple portal tracts in each patient were blindly evaluated and individually scored. We report herein that although IL-12/Th1 and IL-23/Th17 staining were detected in all of the liver sections, they were primarily localized around the damaged interlobular bile ducts in PBC. Most importantly, Th17 skewing was prominent in advanced PBC patients with intensive secretion of IL-23p19 by inflamed hepatocytes around IL-23R, IL-12RB2, and IFN-γ expressing degenerated cholangiocytes. Our novel finding on the direct association of Th17 skewing and disease severity illustrates the significance of the IL-23/Th17 pathway in the perpetuation of IL-12/Th1-mediated immunopathology in PBC. Furthermore, localized IL-23p19 production by hepatocytes may enhance pro-fibrotic Th17 signaling and pro-inflammatory IFN-γ production that contribute to PBC pathology. In conclusion, our data emphasize the pathogenic relevance of IL-12/Th1 and IL-23/Th17 in the evolution of PBC. Of significance, however, the shift from a Th1 to a Th17 imbalance at advanced stages of the disease suggests the necessity to consider modulation of the IL-23/Th17 pathway as a potential target for therapeutic intervention.

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Section: Discussionmentioning

confidence: 61%

IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy

et al. 2014

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“…Mice transgenic for directed expression of dnTGFbRII, under the control of the CD4 promoter lacking the CD8 silencer, spontaneously develop IBD and reveal inflammatory infiltration of the large intestine (27,28). As shown in Fig.…”

Section: Mir-193a-3p Reduces the Intestinal Inflammatory Response In mentioning

confidence: 98%

MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1

Dai

Chen

et al. 2015

Journal of Biological Chemistry

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Background:The involvement of miRNAs in the host mucosal immune response to gut microbes in colitis is still unclear.Results: miR-193a-3p down-regulates PepT1, and intracolonic-delivery of miR-193a-3p ameliorated the severity of colitis. Conclusion: miRNA-193a-3p can target colonic PepT1 and reduce intestinal inflammation. Significance: Our study illustrates the new role of miRNAs in regulating the host immune response to microbes during colitis.

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“…Further, IL-12p35 −/− dnTGF-βRII mice demonstrated a distinct cytokine profile characterized by a shift from a prototype Th1 to a Th17 response associated with readily detectable occurrence of liver fibrosis, suggesting the involvement of a Th17 effector response in the development of biliary fibrosis [8]. However, it was reasoned that the mechanisms associated with biliary epithelial cell autoimmunity is complex and it remained unclear given the fact that depletion of IL-23 led to no marked pathologic changes in the liver of dnTGF-βRII mice [9].…”

Section: Introductionmentioning

confidence: 99%

Identification of Potential Cytokine Pathways for Therapeutic Intervention in Murine Primary Biliary Cirrhosis

et al. 2013

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Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, with the most highly directed and specific autoantibody in both murine and human autoimmunity, the anti-mitochondrial autoantibody (AMA). However, therapeutic advances in this disease have lagged behind. Herein we have taken advantage of our unique model of murine PBC in which mice immunized with 2-octynoic acid coupled to BSA (2OA-BSA), a compound identified by quantitative structure activity relationships (QSAR) of human AMA binding, develop an intense inflammatory cholangitis with striking similarities to humans with PBC. In particular, we have constructed several unique gene-deleted mice, including mice deleted of IL-12p40, IL-12p35, IFN-γ, IL-23p19, IL-17A, IL-17F and IL-22, immunized these animals with 2OA-BSA and followed the natural history of immunopathology to identify key pathways that might provide clues for successful therapy. Our data indicate that whereas both IL-12/Th1 and IL-23/Th17 are involved in cholangitis, it is the IL-12/Th1 signaling pathway that elicits pathology. In fact, deletion of IFN-γ prevents disease and suppresses autoantibodies. Importantly, deletion of the Th17 cytokines IL-17A and IL-22, but not IL-17F, reduces biliary damage; IL-17A-knockout mice have reduced levels of anti-mitochondrial antibody. We further demonstrate that the production of IFN-γ is significantly decreased in the liver of IL-23p19−/−, IL-17A−/− and IL-22−/− mice compared with controls. However, the ability of T cells to produce IFN-γ was not affected in Th17 cytokine-deficient mice. Our data indicate that a deficient Th17 pathway suppresses the accumulation of IFN-γ producing cells in liver during the early phase of cholangitis. In conclusion, whereas IFN-γ has a pivotal role in the early events involved in the pathogenesis of autoimmune cholangitis induced by 2OA-BSA, the IL-23/Th17 pathway potentiates the effects of IL-12/IFN-γ-mediated immunopathology.

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The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type ii mice

Cited by 39 publications

References 35 publications

IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy

IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy

MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1

Identification of Potential Cytokine Pathways for Therapeutic Intervention in Murine Primary Biliary Cirrhosis

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