The FASEB Journal, Vol 7, 369-374, Copyright © 1993 by The Federation of American Societies for Experimental Biology

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A 1-hour pulse with IL-1 beta induces formation of nitric oxide and inhibits insulin secretion by rat islets of Langerhans: evidence for a tyrosine kinase signaling mechanism

JA Corbett, MA Sweetland, JR Lancaster Jr and ML McDaniel
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110.

Nitric oxide has been implicated as the effector molecule that mediates interleukin-1 beta (IL-1 beta)-induced inhibition of glucose-stimulated insulin secretion by rat islets. Brief exposures of islets (1 h) to IL- 1 beta have been shown to inhibit glucose-stimulated insulin secretion at 8 or 18 h after removal of this cytokine. The purpose of this investigation was to determine if brief exposures of islets to IL-1 beta are sufficient to induce the formation of nitric oxide and to examine the signaling process associated with IL-1 beta-induced expression of nitric oxide synthase. We demonstrate that a 1-h pretreatment of islets with IL-1 beta followed by an 8-h incubation in the absence of this cytokine results in inhibition of glucose- stimulated insulin secretion (50%), which is completely prevented by pretreatment of islets with the nitric oxide synthase inhibitor NG- monomethyl-L-arginine (NMMA). The production of nitric oxide by islets under these pulse conditions is demonstrated by IL-1 beta-induced nitrite and electron paramagnetic resonance-detectable iron-nitrosyl complex formation, both of which are prevented by NMMA. IL-1 beta initiates a signal transduction process resulting in the expression of nitric oxide synthase. The signaling process appears to require the activation of a tyrosine kinase, since the tyrosine kinase inhibitor genistein prevents both IL-1 beta-induced inhibition of insulin secretion by islets and formation of nitric oxide by the insulinoma cell line RINm5F. These results show that short exposures of islets to IL-1 beta are sufficient to induce the formation of nitric oxide resulting in inhibition of glucose-stimulated insulin secretion and that a tyrosine kinase may participate in the early signaling events required for IL-1 beta to induce the expression of nitric oxide synthase.

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