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

J Autoimmun. 2013 Mar:41:111-9. doi: 10.1016/j.jaut.2012.12.013. Epub 2013 Feb 8.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / immunology
  • Apoptosis Regulatory Proteins / metabolism
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cholangitis / genetics
  • Cholangitis / immunology
  • Cholangitis / metabolism
  • Cytokines / immunology*
  • Cytokines / metabolism
  • Flow Cytometry
  • Gene Expression / immunology
  • Humans
  • Inflammation Mediators / immunology*
  • Inflammation Mediators / metabolism
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Liver / immunology
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis, Biliary / genetics
  • Liver Cirrhosis, Biliary / immunology
  • Liver Cirrhosis, Biliary / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / immunology*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA-Binding Proteins / immunology
  • RNA-Binding Proteins / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / immunology*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Apoptosis Regulatory Proteins
  • Cytokines
  • Inflammation Mediators
  • Interleukin-17
  • MIRN21 microRNA, mouse
  • MicroRNAs
  • Pdcd4 protein, mouse
  • RNA-Binding Proteins
  • Receptors, Transforming Growth Factor beta
  • Interferon-gamma
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II