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A Protective Role for Heme Oxygenase Expression in Pancreatic Islets Exposed to Interleukin-1ß¹

Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, the State University of New York, Buffalo, New York 14214

Address all correspondence and requests for reprints to: Dr. S. Laychock, 102 Farber Hall, the State University of New York at Buffalo, School of Medicine, Buffalo, New York 14214. E-mail: laychock{at}acsu.buffalo.edu

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-1ß (IL-1ß) induced HO-1 expression above control levels. N^G-monomethyl-L-arginine inhibited the IL-1ß-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-1ß 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-1ß but did not affect HO-1 expression or the inhibitory response to IL-1ß alone. ZnPP also inhibited the protective effect of hemin in IL-1ß-treated islets. CoCl₂ inhibited the marked increase in islet nitrite production in response to IL-1ß. Cobalt-protoporphyrin IX (CoPP), which increased HO expression and activity, also protected islets from the inhibitory effects of IL-1ß, even though IL-1ß largely blocked the CoPP-induced increase in HO-1 expression. In ßHC9 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-1ß. HO-1 may be protective of ß-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.

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