INTERLEUKIN-1-BETA-INDUCED RAT PANCREATIC-ISLET NITRIC-OXIDE SYNTHESIS REQUIRES BOTH THE P38 AND EXTRACELLULAR SIGNAL-REGULATED KINASE-1 2 MITOGEN-ACTIVATED PROTEIN-KINASES/

Interleukin-1 beta (IL-1 beta) is cytotoxic to rat pancreatic beta-cel ls by inhibiting glucose oxidation, causing DNA damage and inducing ap optosis, Nitric oxide (NO) is a necessary but not sufficient mediator of these effects. IL-1 beta induced kinase activity toward Elk-1, acti vation transcription factor 2, c-Jun, and heat shock protein 25 in rat islets. By Western blotting with phosphospecific antibodies and by im munocomplex kinase assay, IL-1 beta was shown to activate extracellula r signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (p38) in islets and rat insulinoma cells. Specific ERK1/2 and p 38 inhibitors individually reduced but in combination blocked IL-1 bet a-mediated islet NO synthesis, and reverse transcription-polymerase ch ain reaction of inducible NO synthase mRNA showed that ERK1/2 and p38 controlled IL-1 beta-induced islet inducible NO synthase expression at the transcriptional level. Hyperosmolarity caused phosphorylation of Elk-1, activation transcription factor 2, and heat shock protein 25 an d activation of ERK1/2 and p38 in islets comparable to that induced by IL-1 beta but did not lead to NO synthesis. Inhibition of p38 but not of ERK1/2 attenuated IL-1 beta-mediated inhibition of glucose-stimula ted insulin release, We conclude that ERK1/2 and p38 activation is nec essary but not sufficient for IL-1 beta-mediated beta-cell NO synthesi s and that p38 is involved in signaling of NO-independent effects of I L-1 beta in beta-cells.