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1,25-Dihydroxyvitamin D₃ Protects RINm5F and Human Islet Cells against Cytokine-Induced Apoptosis: Implication of the Antiapoptotic Protein A20

Cellular Therapy of Diabetes, Institut National de la Santé et de la Recherche Médicale, Equipe de Recherche et d’Innovation Méthodologique 0106 (R.R., B.V., J.K.C., B.L., V.G., T.B., M.D., F.P.), and Institut National de la Santé et de la Recherche Médicale Unité 459 (E.M., P.S.), Faculté de Médecine, 59045 Lille, France

Address all correspondence and requests for reprints to: B. Vandewalle, Thérapie Cellulaire du Diabète, Institut National de la Santé et de la Recherche Médicale, Equipe de Recherche et d’Innovation Méthodologique 0106, Faculté de Médecine, Place de Verdun, 59045 Lille, France. E-mail: bvandewalle{at}univ-lille2.fr.

Transplantation of islets of Langerhans is a potential cure for type 1 diabetes, but its success is hampered by destruction of the islets. The data presented herein suggest that the active metabolite of vitamin D₃ [1,25-(OH)₂D₃] may promote islet cell survival by modulating the effects of inflammatory cytokines, which contribute to ß-cell demise. We investigated some of the mechanisms triggering the apoptotic machinery in rat insulinoma RINm5F cells and human islets treated with IL-1ß plus interferon- plus TNF and assessed the effects of 1,25-(OH)₂D₃ in these processes. Mitochondrial transmembrane permeability and apoptotic features, determined by percentage of sub-G1 cells, quantitation of DNA strand breaks, and Hoechst staining, were significantly increased by cytokines and reverted toward control values by 1,25-(OH)₂D₃ cotreatment. The cytoprotection of cells correlated with the abrogation of cytokine-induced nitric oxide production. The activation of nuclear factor-B plays a key role in the different pathways implicated in nitric oxide generation. We demonstrated for the first time, in both RINm5F cells and human islets, that 1,25-(OH)₂D₃ was able to induce and maintain high levels of A20, an antiapoptotic protein known to block nuclear factor-B activation. Our study showed a clear efficiency of 1,25-(OH)₂D₃ on the apoptotic machinery triggered by cytokines in ß-cells and suggests that 1,25-(OH)₂D₃ could help overcome a major obstacle encountered in the cellular therapy of diabetes, such as nonfunction in the immediate posttransplantation period.

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