1. Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse.
- Author
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Ando Y, Yang GX, Kenny TP, Kawata K, Zhang W, Huang W, Leung PS, Lian ZX, Okazaki K, Ansari AA, He XS, Invernizzi P, Ridgway WM, Lu Q, and Gershwin ME
- Subjects
- 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 metabolism, Flow Cytometry, Gene Expression immunology, Humans, 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, Protein Serine-Threonine Kinases genetics, 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 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Cytokines immunology, Inflammation Mediators immunology, MicroRNAs immunology, Protein Serine-Threonine Kinases immunology, Receptors, Transforming Growth Factor beta 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 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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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