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 . 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,. "
[Show abstract][Hide abstract]ABSTRACT: Macrophages function as sentinel cells, which constantly monitor the host environment for infection or injury. Macrophages have been shown to exhibit a spectrum of activated phenotypes, which can often be categorised under the M1/M2 paradigm. M1 macrophages secrete proinflammatory cytokines and chemokines, such as TNF-
, IL-6, IL-12, CCL4, and CXCL10, and induce phagocytosis and oxidative dependent killing mechanisms. In contrast, M2 macrophages support wound healing and resolution of inflammation. In the past decade, interest has grown in understanding the mechanisms involved in regulating macrophage activation. In particular, epigenetic control of M1 or M2 activation states has been shown to rely on posttranslational modifications of histone proteins adjacent to inflammatory-related genes. Changes in methylation and acetylation of histones by methyltransferases, demethylases, acetyltransferases, and deacetylases can all impact how macrophage phenotypes are generated. In this review, we summarise the latest advances in the field of epigenetic regulation of macrophage polarisation to M1 or M2 states, with particular focus on the cytokine and chemokine profiles associated with these phenotypes.
Full-text · Article · Apr 2016 · Mediators of Inflammation
"Ethanol impairs hepatic regeneration by acting directly as a hepatotoxin and dysregulating numerous important hepatic functions . Some major areas of recent research have emphasized the pathogenesis of ALD through oxidative stress, glutathione depletion, abnormal methionine metabolism, malnutrition, the leakage of intestinal endotoxins, lipopolysaccharide (LPS) signaling, innate immunity, and transcription factors        . "
[Show abstract][Hide abstract]ABSTRACT: Alcoholic liver disease affects a great number of people worldwide. With limited therapeutic options, stem cell therapy offers significant potential for these patients. To date, a limited number of clinical trials have produced transient clinical responses to cell therapy in patients with alcoholic liver disease. Stem cell therapy to reorganize the postnatal liver is an important theme and mission for patients with chronic liver disorders including alcoholic liver injury. We therefore should redevelop the evidence of cell-based liver regeneration therapy, focusing on targets (disease, patient's status and hepatic function), materials (cells, cytokines and genes), and methodology (stem cell types and their derived microparticles, transplantation route, implantation technology and tissue engineering). In this review, we summarize the recent findings regarding the experimental and clinical use of mesenchymal and liver stem cells, focusing mainly on the treatment of alcoholic liver disorders and their relevance in the field of regenerative medicine, and advances on the role of microvesicles and exosomes in this process. We discuss new advances in stem cell therapy from liver regeneration to liver re-organization, which is involved in the recent progress of on-going clinical trials, basic research in stem cell therapy and liver regeneration, and updated exosomes/microvesicles recovery/repairing technology.
Full-text · Article · Jan 2014 · Digestive and Liver Disease
"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. "
[Show abstract][Hide abstract]ABSTRACT: The role of sirtuin-1 (SIRT1) in innate immunity, and in particular the influence of SIRT1 on antimicrobial defense against infection, has yet to be reported but is important to define since SIRT1 inhibitors are being investigated as therapeutic agents in the treatment of cancer, Huntington's disease, and autoimmune diseases. Given the therapeutic potential of SIRT1 suppression, we sought to characterize the role of SIRT1 in host defense. Utilizing both pharmacologic methods and a genetic knockout, we demonstrate that SIRT1 expression has little influence on macrophage and neutrophil antimicrobial functions. Myeloid SIRT1 expression does not change mortality in gram-negative toxin-induced shock or gram-positive bacteremia, suggesting that therapeutic suppression of SIRT1 may be done safely without suppression of myeloid cell-specific immune responses to severe bacterial infections.