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-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.
Corbett
J A
JA
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110.
Sweetland
M A
MA
Lancaster
J R
JR
McDaniel
M L
ML
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D019323:omega-N-Methylarginine
D007328:Insulin; D007375:Interleukin-1; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D011505:Protein-Tyrosine Kinases