A protective role for heme oxygenase expression in pancreatic islets exposed to interleukin-1β

Heme oxygenase (HO)-1 expression was investigated in rat isolated pancreatic islets. Freshly isolated islets showed no evidence of HO-1 expression. After a 20-h culture, there was a small increase in HO-1 in control islets, and interleukin-1β (IL-1β) induced HO-1 expression above control levels. N(G)-monomethyl-L-arginine inhibited the IL-1β-induced increase in HO-1. Sodium nitroprusside-generated nitric oxide also increased HO-1 expression. CoCl₂ induced a concentration- and time-dependent increase in HO-1, but not heat shock protein 70, expression. Cobalt chloride (CoCl₂) protected islets from the inhibitory effects of IL-1β on glucose-stimulated insulin release and glucose oxidation. Nickel chloride did not mimic the effects of CoCl₂. An inhibitor of HO-1 activity, zinc-protoporphyrin IX (ZnPP), prevented the protective effect of CoCl₂ on insulin release with IL- 1β but did not affect HO-1 expression or the inhibitory response to IL-1β alone. ZnPP also inhibited the protective effect of hemin in IL-1β-treated islets. COCl₂ inhibited the marked increase in islet nitrite production in response to IL-1β. Cobalt-protoporphyrin IX (CoPP), which increased HO expression and activity, also protected islets from the inhibitory effects of IL-1β, even though IL-1β largely blocked the CoPP-induced increase in HO-1 expression. In βHC9 cells, CoCl₂ increased HO-1 expression and HO activity, whereas CoPP directly activated HO. ZnPP inhibited basal and CoCl₂- stimulated HO activity. Thus, increased HO-1 expression and/or HO activity in response to CoCl₂, CoPP, and hemin, seems to mediate protective responses of pancreatic islets against IL-1β. HO-1 may be protective of β-cells because of the scavenging of free heme, the antioxidant effects of the end-product bilirubin, or the generation of carbon monoxide, which might have insulin secretion-promoting effects and inhibitory effects on nitric oxide synthase.