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

Type 1 diabetes mellitus is an autoimmune disease resulting from apoptotic destruction of pancreatic β-cells. The activation of inducible nitric oxide synthase (iNOS) by inflammatory cytokines is considered a mediator of destruction in β-cells. Recent findings showed that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), whose distribution was identified in pancreatic neurons, inhibited nitric oxide (NO) production in cytokine-activated macrophages. In the present study, we investigated the cytoprotective effect of PACAP in the cytokine-exposed mice β-cell line, βTC cells. 1 x 10^-8 M PACAP inhibited the reduction of cell viability, NO production, expression of iNOS mRNA, and iNOS promoter activity caused by the combination of three proinflammatory cytokines. Selective iNOS inhibitor also showed the cytoprotective effect in βTC cells. These data suggested that PACAP has a cytoprotective effect in cytokine-treated β-cells through inhibition of iNOS transcription. (C) 2000 Academic Press.