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

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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

Fingerprint

MicroRNAs
Cytokines
T-Lymphocytes
Cholangitis
Biliary Liver Cirrhosis
Up-Regulation
Apoptosis Regulatory Proteins
Interleukin-17
T-Lymphocyte Subsets
Colitis
T-Cell Antigen Receptor
Autoimmunity
Down-Regulation
Spleen
Lymph Nodes
Apoptosis
Phenotype
Liver

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse. / Ando, Yugo; Yang, Guo Xiang; Kenny, Thomas P.; Kawata, Kazuhito; Zhang, Weici; Huang, Wenting; Leung, Patrick S; Lian, Zhe Xiong; Okazaki, Kazuichi; Ansari, Aftab A.; He, Xiaosong; Invernizzi, Pietro; Ridgway, William M.; Lu, Qianjin; Gershwin, M. Eric.

In: Journal of Autoimmunity, Vol. 41, 03.2013, p. 111-119.

Research output: Contribution to journalArticle

Ando, Y, Yang, GX, Kenny, TP, Kawata, K, Zhang, W, Huang, W, Leung, PS, Lian, ZX, Okazaki, K, Ansari, AA, He, X, Invernizzi, P, Ridgway, WM, Lu, Q & Gershwin, ME 2013, 'Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse', Journal of Autoimmunity, vol. 41, pp. 111-119. https://doi.org/10.1016/j.jaut.2012.12.013
Ando, Yugo ; Yang, Guo Xiang ; Kenny, Thomas P. ; Kawata, Kazuhito ; Zhang, Weici ; Huang, Wenting ; Leung, Patrick S ; Lian, Zhe Xiong ; Okazaki, Kazuichi ; Ansari, Aftab A. ; He, Xiaosong ; Invernizzi, Pietro ; Ridgway, William M. ; Lu, Qianjin ; Gershwin, M. Eric. / Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse. In: Journal of Autoimmunity. 2013 ; Vol. 41. pp. 111-119.
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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.",
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AU - Ando, Yugo

AU - Yang, Guo Xiang

AU - Kenny, Thomas P.

AU - Kawata, Kazuhito

AU - Zhang, Weici

AU - Huang, Wenting

AU - Leung, Patrick S

AU - Lian, Zhe Xiong

AU - Okazaki, Kazuichi

AU - Ansari, Aftab A.

AU - He, Xiaosong

AU - Invernizzi, Pietro

AU - Ridgway, William M.

AU - Lu, Qianjin

AU - Gershwin, M. Eric

PY - 2013/3

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N2 - 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.

AB - 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.

KW - Autoimmunity

KW - Cholangitis

KW - Colitis

KW - Inflammatory bowel disease

KW - MicroRNA

KW - MiR-21

KW - Primary biliary cirrhosis

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