title: Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway.
abstract: OBJECTIVE
  SIRT1, a class III histone/protein deacetylase, is known to interfere with the nuclear factor-kappaB (NF-kappaB) signaling pathway and thereby has an anti-inflammatory function. Because of the central role of NF-kappaB in cytokine-mediated pancreatic beta-cell damage, we postulated that SIRT1 might work in pancreatic beta-cell damage models.
  
  
  METHODS
  RINm5F (RIN) cells or isolated rat islets were treated with interleukin-1beta and interferon-gamma. 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-kappaB 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 beta-cell destruction but also into the regulation of SIRT1 as a possible target to attenuate cytokine-induced beta-cell damage.
authors.affiliation: Department of Biochemistry, Medical School and Diabetes Research Center, Chonbuk National University, Jeonju, Jeonbuk, Korea.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Song
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Song
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Woo Sung
authors.initials: WS
authors.lastname: Moon
authors.forename: Myung-Kwan
authors.initials: MK
authors.lastname: Han
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Kang-Beom
authors.initials: KB
authors.lastname: Kwon
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D000077185:Resveratrol; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D016328:NF-kappa B; D013267:Stilbenes; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol