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OBJECTIVE-SIRT1, a class III histone/protein deacetylase, is known to interfere with the nuclear factor-κB (NF-κB) signaling pathway and thereby has an anti-inflammatory function. Because of the central role of NF-κB in cytokine-mediated pancreatic β-cell damage, we postulated that SIRT1 might work in pancreatic β-cell damage models.
RESEARCH DESIGN AND METHODS-RINm5F (RIN) cells or isolated rat islets were treated with interleukin-lβ and interferon-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 the inducible form of nitric oxide (NO) synthase (iNOS) and NO production. However, SIRT1 overexpression completely prevented cytokine-mediated cytotoxicity, NO production, and iNOS expression. The molecular mechanism by which SIRT1 inhibits iNOS expression appeared to involve the inhibition of the NF-κB signaling pathway through deacetylation of p65. In addition, SIRT1 activation by either resveratrol or adenoviraldirected overexpression of SIRTl 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 ß-cell destruction but also into the regulation of SIRTl as a possible target to attenuate cytokine-induced β-cell damage. Diabetes 58:344-351, 2009
Diabetes, which is characterized at the cellular level by a deficit in β-cell mass, is increasing to epidemic proportions. However, the mechanisms underlying β-cell destruction are not clear, although it has been suggested that cytokines may be involved. For example, in type 1 diabetes, cytokines are important mediators in the impaired function and destruction of pancreatic β-cells. In pancreatic islets, interleukin (IL)-I β, either alone or in combination with interferon (IFN)-7, causes the production of nitric oxide (NO) through the inducible form of NO synthase (iNOS) (1-4).
IL-1β exerts its primary effects through the transcriptional nuclear factor-κB (NF-κB) pathway. NF-κB is initially located in the cytoplasm in an inactive form complexed with inhibitor of κB (IκB), an inhibitory factor of NF-κB. Various inducers can cause dissociation of this complex, presumably by phosphorylation of IkB, resulting in NF-κB being released from the complex. NF-κB then translocates to the nucleus, where it interacts with specific DNA recognition sites to mediate gene transcription such as iNOS and...