Role of SIRT1 in regulation of LPS- or two ethanol metabolites-induced TNF-α production in cultured macrophage cell lines
ABSTRACT 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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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.Digestive and Liver Disease 01/2014; 46(5). DOI:10.1016/j.dld.2013.11.015 · 2.89 Impact Factor
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ABSTRACT: Certain cytokines, the prototype being the highly pleiotropic TNF, have many homeostatic physiological roles, are involved in innate immunity, and cause inflammation when in excess. These cytokines have long been accepted to have central roles in the pathogenesis of systemic or local non-cerebral disease states, whether acute or chronic, and whether or not caused by infectious agents. Over the last decade they have also been appreciated to be broadly important in brain physiology. As in other organs, excessive levels in brain are harmful, and its physiological complexity leads to correspondingly complex dysfunction. This review summarizes the burgeoning literature on this topic, and how the functions of these molecules, particularly TNF, are influencing the outlook of researchers on the pathophysiology of these diseases. Basic brain physiology is thus informing knowledge of the brain dysfunction that characterizes such apparently diverse states as Alzheimer's disease, trauma (mostly, but not only, to the brain), Parkinson's disease, and severe systemic infectious states, including malaria, sepsis, viral diseases and major depression. The implication is that the anti-cytokine therapies now in use, typically directed at TNF, warrant testing in these diseases in circumstances in which the therapeutic agent enters the cerebrospinal fluid. Routinely administering such drugs to patients exhibiting the neurological changes discussed in this review would simply add another organ system to what is already a very successful strategy in the treatment of inflammatory disease at other sites, such as joints, skin and gut. Clearly, the most relevant research is focussed on Alzheimer's disease, but the principles may also apply to other encephalopathies.Pharmacology [?] Therapeutics 12/2010; 128(3):519-48. DOI:10.1016/j.pharmthera.2010.08.007 · 7.75 Impact Factor
- Atherosclerosis Supplements 06/2010; 11(2):22-22. DOI:10.1016/S1567-5688(10)70095-7 · 9.67 Impact Factor