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

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.

• Authors: Yugo Ando, Guo-Xiang Yang, Thomas P Kenny, Kazuhito Kawata, Weici Zhang, Wenting Huang, Patrick S C Leung, Zhe-Xiong Lian, Kazuichi Okazaki, Aftab A Ansari, Xiao-Song He, Pietro Invernizzi, William M Ridgway, Qianjin Lu, M Eric Gershwin
• Journal: Journal of autoimmunity (J Autoimmun) Vol. 41 Pg. 111-9 (Mar 2013) ISSN: 1095-9157 [Electronic] England
• PMID: 23395552 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• 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

Topics

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