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

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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.

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This work was supported by the Danish Diabetes Association and Novo Nordisk.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Postdoctoral Fellowship from Juvenile Diabetes Foundation International.

Supported by NIH Grant AI 15614.