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

Nitric oxide has been implicated as the effector molecule that mediates interleukin-1beta (IL-1beta)-induced inhibition of glucose-stimulated insulin secretion by rat islets. Brief exposures of islets (1 h) to IL-1beta 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-1beta are sufficient to induce the formation of nitric oxide and to examine the signaling process associated with IL-1beta-induced expression of nitric oxide synthase. We demonstrate that a 1-h pretreatment of islets with IL-1beta 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 N(G)-monomethyl-L-arginine (NMMA). The production of nitric oxide by islets under the se pulse conditions is demonstrated by IL-1beta-induced nitrite and electron paramagnetic resonance-detectable iron-nitrosyl complex formation, both of which are prevented by NMMA. IL-1beta 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-1beta-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-1beta 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-1beta to induce the expression of nitric oxide synthase.