Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse

• Type of Material: Article
• Authors: Yugo Ando, University of California; Guo-Xiang Yang, University of California; Thomas P. Kenny, University of California; Kazuhito Kawata, University of California; Weici Zhang, University of California; Wenting Huang, University of Cincinnati; Patrick S.C. Leung, University of California; Zhe-Xiong Lian, University of California; Kazuichi Okazaki, Kansai Medical University; Aftab A Ansari, Emory University; Xiao-Song He, University of California; Pietro Invernizzi, University of California; William M. Ridgway, University of Cincinnati; Qianjin Lu, Central South University; M. Eric Gershwin, University of California
• Language: English
• Date: 2013-03
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaut.2012.12.013
• Title of Journal or Parent Work: Journal of Autoimmunity
• ISSN: 0896-8411
• Volume: 41
• Start Page: 111
• End Page: 119
• Grant/Funding Information: Financial support provided by National Institutes of Health grant DK090019.
• Keywords: microRNA; Primary biliary cirrhosis; miR-21; cholangitis; autoimmunity; inflammatory bowel disease; colitis
• Research Categories: Health Sciences, Immunology

Abstract

Dominant negative TGF-β receptor II (dnTGF-βRII) mice spontaneously develop an autoimmune cholangitis resembling human primary biliary cirrhosis (PBC). Interestingly, the dominant negative TGF-β receptor is expressed by both CD4+ and CD8+ T cells and leads to greatly reduced (but not absent) TGF-β 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-β signaling is intimately involved with miRNA biogenesis and control. Herein we show that lack of T cell TGF-β signaling leads to down regulation of T cell miRNAs but upregulation 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-βRII mice. Previous studies indicate that miR-21 increases the synthesis of IFN-γ 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 upregulation of the inflammatory cytokines TNF-α and IFN-γ, thus partly replicating the dnTGF-βRII T cell phenotype. In conclusion, these data suggest miR-21 plays a critical role in the production of pro-inflammatory cytokines in dnTGFβRII 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.