Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor {alpha} (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease
Authors
Bala, ShashiMarcos, Miguel
Kodys, Karen
Csak, Timea
Catalano, Donna
Mandrekar, Pranoti
Szabo, Gyongyi
UMass Chan Affiliations
Department of Medicine, Division of GastroenterologyDocument Type
Journal ArticlePublication Date
2011-01-14
Metadata
Show full item recordAbstract
Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) and Toll-Like Receptors 4 (TLR4)-LPS-mediated increase in TNFalpha 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 TNFalpha induction. In a mouse model of alcoholic liver disease, we found a significant increase in both miR-155 levels and TNFalpha production in isolated KCs when compared with pair-fed controls. The mechanistic role of miR-155 in TNFalpha regulation was indicated by decreased TNFalpha levels in alcohol-treated macrophages after inhibition of miR-155 and by increased TNFalpha production after miR-155 overexpression, respectively. We found that miR-155 affected TNFalpha mRNA stability because miR-155 inhibition decreased whereas miR-155 overexpression increased TNFalpha mRNA half-life. Using the NF-kappaB inhibitors, MG-132 or Bay11-7082, we demonstrated that NF-kappaB 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-kappaB and the increased miR-155 contributes to alcohol-induced elevation in TNFalpha production via increased mRNA stability.Source
J Biol Chem. 2011 Jan 14;286(2):1436-44. Epub 2010 Nov 9. Link to article on publisher's siteDOI
10.1074/jbc.M110.145870Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31171PubMed ID
21062749Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M110.145870