EBSELEN AND CYTOKINE-INDUCED NITRIC-OXIDE SYNTHASE EXPRESSION IN INSULIN-PRODUCING CELLS

Interleukin-1 (IL-1) may be a mediator of beta-cell damage in insulin- dependent diabetes mellitus (IDDM). The IL-1 mechanism of action on in sulin-producing cells probably includes activation of the transcriptio n nuclear factor kappa B (NF-kappa B), increased transcription of the inducible form of nitric oxide synthase (iNOS) and the subsequent prod uction of nitric oxide (NO). Reactive oxygen intermediates, particular ly H2O2, have been proposed as second messengers for NF-kappa B activa tion. In the present study, we tested whether ebselen (2-phenyl-1,2-be nzisoselenazol-3(2H)-one), a glutathione peroxidase mimicking compound , could counteract the effects of IL-1 beta, H2O2 and alloxan in rat p ancreatic islets and in the rat insulinoma cell line RINm5F (RIN cells ). Some of these experiments were also reproduced in human pancreatic islets. Ebselen (20 mu M) prevented the increase in nitrite production by rat islets exposed to IL-1 beta for 6 hr and induced significant p rotection against the acute inhibitory effects of alloxan or H2O2 expo sure, as judged by the preserved glucose oxidation rates. However, ebs elen failed to prevent the increase in nitrite production and the decr ease in glucose oxidation and insulin release by rat islets exposed to IL-1 beta for 24 hr. Ebselen prevented the increase in nitrite produc tion by human islets exposed for 14 hr to a combination of cytokines ( IL-1 beta, tumor necrosis factor-alpha and interferon-gamma). In RIN c ells, ebselen counteracted both the expression of iNOS mRNA and the in crease in nitrite production induced by 6 hr exposure to IL-beta but f ailed to block IL-1 beta-induced iNOS expression following 24 hr expos ure to the cytokine. Moreover, ebselen did not prevent IL-1 beta-induc ed NF-kappa B activation. As a whole, these data indicate that ebselen partially counteracts cytokine-induced NOS activation in pancreatic b eta-cells, an effect not associated with inhibition of NF-kappa B acti vation. Copyright (C) 1996 Elsevier Science Inc.