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Int. J. Mol. Sci. 2016, 17(7), 1076; doi:10.3390/ijms17071076

MicroRNA-146a-5p Negatively Regulates Pro-Inflammatory Cytokine Secretion and Cell Activation in Lipopolysaccharide Stimulated Human Hepatic Stellate Cells through Inhibition of Toll-Like Receptor 4 Signaling Pathways

1
Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
2
Division of Radiation Oncology, Departments of Oncology, National Taiwan University Hospital, Taipei 100, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: Martin Pichler
Received: 30 May 2016 / Revised: 20 June 2016 / Accepted: 28 June 2016 / Published: 7 July 2016
(This article belongs to the Collection Regulation by Non-Coding RNAs)
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Abstract

Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB). Knockdown of IRAK1 and TRAF6 also suppressed pro-inflammatory cytokine production by inhibiting NF-κB phosphorylation. In addition, miR-146a-5p mimic blocked LPS induced TRAF6 dependent c-Jun N-terminal kinase (JNK) and Smad2 activation as well as α-SMA production. Taken together, these results suggest that miR-146a-5p suppresses pro-inflammatory cytokine secretion and cell activation of HSC through inhibition of TLR4/NF-κB and TLR4/TRAF6/JNK pathway. View Full-Text
Keywords: hepatic fibrosis; inflammation; toll like receptor 4; microRNA-146a hepatic fibrosis; inflammation; toll like receptor 4; microRNA-146a
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Chen, Y.; Zeng, Z.; Shen, X.; Wu, Z.; Dong, Y.; Cheng, J.C.-H. MicroRNA-146a-5p Negatively Regulates Pro-Inflammatory Cytokine Secretion and Cell Activation in Lipopolysaccharide Stimulated Human Hepatic Stellate Cells through Inhibition of Toll-Like Receptor 4 Signaling Pathways. Int. J. Mol. Sci. 2016, 17, 1076.

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