Overexpression of SIRT1 protects pancreatic β-cells against cytokine toxicity through suppressing NF-κB signaling pathway

Objective: SIRT1, a class III histone/protein deacetylase, is known to interfere NF-κB signaling pathway and thereby has an anti-inflammatory function. Due to the central role of NF-κB in cytokine-mediated pancreatic β-cell damage, we postulated that SIRT1 might work in pancreatic β-cell damage model. Research Design and Methods: RINm5F (RIN) cells or isolated rat islets were treated with IL-1β and IFN-γ. SIRT1 was activated by resveratrol, a pharmacological activator, or ectopic overexpression. The underlying mechanisms of SIRT1 against cytokine toxicity were further explored. Results: Treatment of RIN cells with cytokines induced cell damage, and this damage was well correlated with the expression of inducible form of NO synthase (iNOS) and nitric oxide production. However, SIRT1 overexpression completely prevented cytokine-mediated cytotoxicity, as well as nitric oxide production and iNOS expression. The molecular mechanism by which SIRT1 inhibits iNOS gene expression appeared to involve the inhibition of NF-κB signaling pathway through deacetylation of p65. In addition, SIRT1 activation by either resveratrol or adenoviral-directed overexpression of SIRT1 could prevent cytokine toxicity and maintain normal insulin secreting responses to glucose in isolated rat islets. Conclusions: This study will provide valuable information not only into the mechanisms underlying β-cell destruction but also into the regulation of SIRT1 as a possible target to attenuate cytokine-induced β-cell damage. Abbreviations: IL-1β, interleukin-1β; IFN-γ, interferon-γ; NO, nitric oxide; iNOS, inducible form of nitric oxide synthase; NF-κB, nuclear factor κB; IκB, inhibitory factor of NF-κB; RIN, RINm5F; MTT, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; BrdU, 5Bromo-2-deoxyuridine; HDAC, histone/protein deacetylases; MLDS, multiple low-dose streptozotocin; AO, acridine orange