Type 1 diabetes mellitus is an autoimmune disease resulting from apoptotic destruction of pancreatic beta -cells. The activation of inducible nitric oxide synthase (iNOS) by inflammatory cytokines is considered a mediator of destruction in beta -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 beta -cell 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 activity caused by the combination of three proinflammatory cytokines. Selective iNOS inhibitor also showed the cytoprotective effect in beta TC cells. These data suggested that PACAP has a cytoprotective effect in cytokine-treated beta -cells through inhibition of iNOS transcription,