Interleukin-1β-induced Rat Pancreatic Islet Nitric Oxide Synthesis Requires Both the p38 and Extracellular Signal-regulated Kinase 1/2 Mitogen-activated Protein Kinases

• Published in: The Journal of biological chemistry Vol. 273; no. 24; pp. 15294 - 15300
• Main Authors: Larsen, Claus M., Wadt, Karin A.W., Juhl, Lone F., Andersen, Henrik U., Karlsen, Allan E., Su, Michael S.-S., Seedorf, Klaus, Shapiro, Leland, Dinarello, Charles A., Mandrup-Poulsen, Thomas
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 12.06.1998
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.24.15294

Interleukin-1β (IL-1β) is cytotoxic to rat pancreatic β-cells by inhibiting glucose oxidation, causing DNA damage and inducing apoptosis. Nitric oxide (NO) is a necessary but not sufficient mediator of these effects. IL-1β induced kinase activity toward Elk-1, activation transcription factor 2, c-Jun, and heat shock protein 25 in rat islets. By Western blotting with phosphospecific antibodies and by immunocomplex kinase assay, IL-1β was shown to activate extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (p38) in islets and rat insulinoma cells. Specific ERK1/2 and p38 inhibitors individually reduced but in combination blocked IL-1β-mediated islet NO synthesis, and reverse transcription-polymerase chain reaction of inducible NO synthase mRNA showed that ERK1/2 and p38 controlled IL-1β-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 and activation of ERK1/2 and p38 in islets comparable to that induced by IL-1β but did not lead to NO synthesis. Inhibition of p38 but not of ERK1/2 attenuated IL-1β-mediated inhibition of glucose-stimulated insulin release. We conclude that ERK1/2 and p38 activation is necessary but not sufficient for IL-1β-mediated β-cell NO synthesis and that p38 is involved in signaling of NO-independent effects of IL-1β in β-cells.