HEAT-SHOCK INHIBITS CYTOKINE-INDUCED NITRIC-OXIDE SYNTHASE EXPRESSIONBY RAT AND HUMAN ISLETS

In this study the effects of heat shock on interleukin-1 beta (IL-1)-i nduced inhibition of islet metabolic function were examined. Treatment of rat islets for 18 h with IL-1 results in a potent inhibition of gl ucose-stimulated insulin secretion. The inhibitory effects of IL-1 on insulin secretion are completely prevented if islets are pretreated fo r 60 min at 42 C before cytokine stimulation. Heat shock also prevents IL-1-induced inhibition of insulinoma RINm5F cell mitochondrial aconi tase activity. The protective effects of heat shock on islet metabolic function are associated with the inhibition of IL-1-stimulated induci ble nitric oxide synthase (iNOS or NOS II) expression. Islets heat sho cked for 60 min at 42 C fail to express iNOS (messenger RNA or protein ) or produce nitrite in response to IL-1. IL-1-induced iNOS expression by rat islets requires activation of the transcriptional regulator nu clear factor kappa B (NF-kappa B). Heat shock prevents IL-1-induced NF -kappa B nuclear localization by inhibiting inhibitory protein kappa B (I kappa B) degradation in rat islets. Similar to rat islets, heat sh ock (stimulated by 90 min incubation at 42 C) prevents IL-1 + interfer on gamma-induced iNOS expression and NF-kappa B nuclear localization i n human islets. IL-1 also stimulates heat-shock protein 70 (hsp 70) ex pression by rat islets, and hsp 70 expression is dependent on islet pr oduction of nitric oxide. Last, evidence is presented that implicates nitric oxide as a stimulus for the expression of proteins that partici pate in islet recovery from nitric oxide-mediated damage. These studie s indicate that heat shock prevents cytokine-induced islet damage by i nhibiting iNOS expression, and suggest that nitric oxide is one effect or molecule that stimulates the expression of factors involved in beta -cell recovery from nitric oxide-mediated damage.