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

Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 04/2009; 296(5):G1047-53. DOI: 10.1152/ajpgi.00016.2009
Source: PubMed


Dysregulation of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) 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-alpha. In the present study, we examined the role of SIRT1 signaling in TNF-alpha 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-alpha levels. LPS, AcH, and acetate each provoked the release of TNF-alpha 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-alpha release, suggesting that impairment of SIRT1 may contribute to TNF-alpha 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-kappaB) and promotion of NF-kappaB transcriptional activity. Taken together, our findings suggest that SIRT1-NF-kappaB signaling is involved in regulating LPS- and metabolites-of-ethanol-mediated TNF-alpha 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.

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    • "Studies with the Class III HDACs have revealed that members of this enzyme subfamily behave diversely. SIRT1 levels in macrophages are dampened under inflammatory conditions, suggesting that this HDACs and the epigenetic changes it is responsible for are not required for cell activa- tion [71]. Indeed, studies have shown that SIRT1 deficiency in myeloid cells results in increased tissue infiltration of M1 macrophages and augments inflammatory responses, mainly due to NF-kB p65, AP-1, and FAK increased acetylation and increased target gene expression [70,[72][73][74]. "
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    • "Finally, we demonstrate that mice lacking SIRT1 expression in myeloid cells are resistant to endotoxin-induced hypothermia, but succumb to gram-positive bacteremia/sepsis and gram-negative endotoxemia/shock with similar kinetics as WT mice. Previous groups have shown that resveratrol decreases LPS-induced TNFα secretion from RAW cells, while sirtinol amplifies the pro-inflammatory response to LPS [28,29]. In contrast, resveratrol has been shown to induce apoptosis of HL60 cells in a dose-dependent manner303132. "
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