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INFLAMMATION/IMMUNITY/MEDIATORS

Role of SIRT1 in regulation of LPS- or two ethanol metabolites-induced TNF- production in cultured macrophage cell lines

¹Departments of Molecular Pharmacology and Physiology and ²Department of Surgery, James A. Haley Veterans Affairs Medical Center, University of South Florida Health Sciences Center, Tampa, Florida

Submitted 13 January 2009 ; accepted in final form 16 March 2009

Dysregulation of proinflammatory cytokines such as tumor necrosis factor- (TNF-) has been implicated in the pathogenesis of alcoholic liver injury. Sirtuin 1 (SIRT1) is an NAD⁺-dependent class III protein deacetylase that is known to be involved in regulating production of proinflammatory cytokines including TNF-. In the present study, we examined the role of SIRT1 signaling in TNF- generation stimulated by either lipopolysaccharide (LPS), acetaldehyde (AcH), or acetate (two major metabolites of ethanol) in two cultured macrophage cell lines. In both rat Kupffer cell line 1 (RKC1) and murine RAW 264.7 macrophages, treatment with either LPS, AcH, or acetate caused significant decreases in SIRT1 transcription, translation, and activation, which essentially demonstrated an inverse relationship with TNF- levels. LPS, AcH, and acetate each provoked the release of TNF- from RKC1 cells, whereas coincubation with resveratrol (a potent SIRT1 agonist) inhibited this effect. Conversely, addition of sirtinol (a known SIRT1 inhibitor) or knocking down SIRT1 by the small silencing SIRT1 plasmid (SIRT1shRNA) augmented TNF- release, suggesting that impairment of SIRT1 may contribute to TNF- secretion. Further mechanistic studies revealed that inhibition of SIRT1 by LPS, AcH, or acetate was associated with a marked increase in the acetylation of the RelA/p65 subunit of nuclear transcription factor (NF-B) and promotion of NF-B transcriptional activity. Taken together, our findings suggest that SIRT1-NF-B signaling is involved in regulating LPS- and metabolites-of-ethanol-mediated TNF- production in rat Kupffer cells and in murine macrophages. Our study provides new insights into understanding the molecular mechanisms underlying the development of alcoholic steatohepatitis.

inflammation; adiponectin; signal transduction