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

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.