Up-regulation of microRNA-155 in macrophages contributes to increased Tumor Necrosis Factor α (TNFα) production via increased mRNA half-life in alcoholic liver disease

Shashi Bala, Miguel Marcos, Karen Kodys, Timea Csak, Donna Catalano, Pranoti Mandrekar, G. Szabó

Research output: Contribution to journalArticle

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Abstract

Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) and Toll-Like Receptors 4 (TLR4)-LPS-mediated increase in TNFα production has a central role in the pathogenesis of alcoholic liver disease. Micro-RNA (miR)-125b, miR-146a, and miR-155 can regulate inflammatory responses to LPS. Here we evaluated the involvement of miRs in alcohol-induced macrophage activation. Chronic alcohol treatment in vitro resulted in a time-dependent increase in miR-155 but not miR-125b or miR-146a levels in RAW 264.7 macrophages. Furthermore, alcohol pretreatment augmented LPS-induced miR-155 expression in macrophages. We found a linear correlation between alcohol-induced increase in miR-155 and TNFα induction. In a mouse model of alcoholic liver disease, we found a significant increase in both miR-155 levels and TNFα production in isolated KCs when compared with pair-fed controls. The mechanistic role of miR-155 in TNFα regulation was indicated by decreased TNFα levels in alcohol-treated macrophages after inhibition of miR-155 and by increased TNFα production after miR-155 overexpression, respectively. We found that miR-155 affected TNFα mRNA stability because miR-155 inhibition decreased whereas miR-155 overexpression increased TNFα mRNA half-life. Using the NF-κB inhibitors, MG-132 or Bay11-7082, we demonstrated that NF-κB activation mediated the up-regulation of miR-155 by alcohol in KCs. In conclusion, our novel data demonstrate that chronic alcohol consumption increases miR-155 in macrophages via NF-κB and the increased miR-155 contributes to alcohol-induced elevation in TNFα production via increased mRNA stability.

Original languageEnglish
Pages (from-to)1436-1444
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number2
DOIs
Publication statusPublished - Jan 14 2011

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Alcoholic Liver Diseases
Macrophages
MicroRNAs
Liver
Half-Life
Up-Regulation
Tumor Necrosis Factor-alpha
Messenger RNA
Alcohols
Kupffer Cells
Lipopolysaccharides
Chemical activation
RNA Stability
Toll-Like Receptor 4
Macrophage Activation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Up-regulation of microRNA-155 in macrophages contributes to increased Tumor Necrosis Factor α (TNFα) production via increased mRNA half-life in alcoholic liver disease. / Bala, Shashi; Marcos, Miguel; Kodys, Karen; Csak, Timea; Catalano, Donna; Mandrekar, Pranoti; Szabó, G.

In: Journal of Biological Chemistry, Vol. 286, No. 2, 14.01.2011, p. 1436-1444.

Research output: Contribution to journalArticle

Bala, Shashi ; Marcos, Miguel ; Kodys, Karen ; Csak, Timea ; Catalano, Donna ; Mandrekar, Pranoti ; Szabó, G. / Up-regulation of microRNA-155 in macrophages contributes to increased Tumor Necrosis Factor α (TNFα) production via increased mRNA half-life in alcoholic liver disease. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 2. pp. 1436-1444.
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