IL-1.beta. induces the coexpression of both nitric oxide synthase and cyclooxygenase by Islets of Langerhans: activation of cyclooxygenase by nitric oxide

Abstract

Autoimmune diabetes is characterized by an early infiltration of lymphocytes into and around islets, which is followed by selective destruction of the insulin-secreting beta-cell. Cytokines released during this inflammatory reaction have been implicated as effector molecules which mediate beta-cell destruction. In vitro treatment of rat islets with the cytokine IL-1 beta results in an inhibition of glucose-stimulated insulin secretion that is mediated by the overproduction of nitric oxide. IL-1 beta also stimulates the production of the cyclooxygenase (COX) product prostaglandin E2 (PGE2). In this study we have examined the effects of IL-1 beta on both inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (iCOX) expression, and the direct effects of nitric oxide on the activity of COX. Treatment of rat islets with 5 units/mL IL-1 beta induces a similar time-dependent production of both nitrite and PGE2. IL-1 beta-induced nitrite and PGE2 production is attenuated by the NOS inhibitor NG-monomethyl-L-arginine (NMMA), but NMMA has no inhibitory effect on the expression of either iCOX or iNOS as determined by immunoprecipitation. Actinomycin D prevents IL-1 beta-induced iCOX and iNOS expression and the production of both nitrite and PGE2 by islets, suggesting that mRNA transcription is required for IL-1 beta-induced expression of both iNOS and iCOX. The effects of exogenous arachidonic acid on both constitutive COX (cCOX) and iCOX activity were also investigated.(ABSTRACT TRUNCATED AT 250 WORDS)