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

Yugo Ando, Guo Xiang Yang, Thomas P. Kenny, Kazuhito Kawata, Weici Zhang, Wenting Huang, Patrick S Leung, Zhe Xiong Lian, Kazuichi Okazaki, Aftab A. Ansari, Xiaosong He, Pietro Invernizzi, William M. Ridgway, Qianjin Lu, M. Eric Gershwin

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

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 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-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 up-regulation 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 dnTGF-βRII 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.

Original languageEnglish (US)
Pages (from-to)111-119
Number of pages9
JournalJournal of Autoimmunity
Volume41
DOIs
StatePublished - Mar 2013

Keywords

  • Autoimmunity
  • Cholangitis
  • Colitis
  • Inflammatory bowel disease
  • MicroRNA
  • MiR-21
  • Primary biliary cirrhosis

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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