期刊
JOURNAL OF AUTOIMMUNITY
卷 41, 期 -, 页码 111-119出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2012.12.013
关键词
Primary biliary cirrhosis; Inflammatory bowel disease; Autoimmunity; Cholangitis; Colitis; microRNA; miR-21
类别
资金
- National Institutes of Health [DK090019]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK090019] Funding Source: NIH RePORTER
Dominant-negative TGF-beta receptor II (dnTGF-beta RII) mice spontaneously develop an autoimmune cholangitis resembling human primary biliary cirrhosis (PBC). Interestingly, the dominant-negative TGF-beta receptor is expressed by both CD4(+) and CD8(+) T cells and leads to greatly reduced (but not absent) TGF-beta signaling resulting in T cell intrinsic cell mediated autoimmunity. However, the mechanisms of the T cell dysregulation remain unclear. Recently it has been shown that TGF-beta signaling is intimately involved with miRNA biogenesis and control. Herein we show that lack of T cell TGF-beta signaling leads to down regulation of T cell miRNAs but up-regulation of the key inflammatory miRNA 21. Furthermore, the expression of miR-21 from hepatic effector CD8(+) T cells is significantly higher than in the same subsets isolated from spleen and mesenteric lymph nodes of the dnTGF-beta R11 mice. Previous studies indicate that miR-21 increases the synthesis of IFN-gamma and IL-17A by T cells and suppresses apoptosis via programmed cell death protein 4 (PDCD4). Data presented herein demonstrate that transfecting w.t. B6 T cell subsets with miR-21 resulted in up-regulation of the inflammatory cytokines TNF-alpha and IFN-gamma, thus partly replicating the dnTGF-beta RII T cell phenotype. In conclusion, these data suggest miR-21 plays a critical role in the production of pro-inflammatory cytokines in dnTGF-beta RII mice, which could be a contributing factor for the development of the organ-specific autoimmune cholangitis and colitis in this murine model of human PBC. (C) 2013 Elsevier Ltd. All rights reserved.
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