Pituitary adenylate cyclase-activating polypeptide prevents cytokine-induced cytotoxicity via inhibition of inducible nitric oxide synthase expression in beta TC cells

Type 1 diabetes mellitus is an autoimmune disease resulting from apoptotic destruction of pancreatic beta -cells. The activation of inducible nitric o xide synthase (iNOS) by inflammatory cytokines is considered a mediator of destruction in beta -cells. Recent findings showed that the neuropeptide pi tuitary adenylate cyclase-activating polypeptide (PACAP), whose distributio n was identified in pancreatic neurons, inhibited nitric oxide (NO) product ion in cytokine-activated macrophages. In the present study, we investigate d the cytoprotective effect of PACAP in the cytokine-exposed mice beta -cel l line, beta TC cells. 1 x 10(-8) Mi PACAP inhibited the reduction of cell viability, NO production, expression of iNOS mRNA, and iNOS promoter activi ty caused by the combination of three proinflammatory cytokines. Selective iNOS inhibitor also showed the cytoprotective effect in beta TC cells. Thes e data suggested that PACAP has a cytoprotective effect in cytokine-treated beta -cells through inhibition of iNOS transcription, (C) 2000 Academic Pr ess.