Discovery of Molecular Pathways Mediating 1,25-Dihydroxyvitamin D3 Protection Against Cytokine-Induced Inflammation and Damage of Human and Male Mouse Islets of Langerhans

Protection against insulitis and diabetes by active vitamin D, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), in nonobese diabetic mice has until now mainly been attributed to its immunomodulatory effects, but also protective effects of this hormone on inflammation-induced beta-cell death have been reported. The aim of this study was to clarify the molecular mechanisms by which 1,25(OH)(2)D-3 contributes to beta-cell protection against cytokine-induced beta-cell dysfunction and death. Human and mouse islets were exposed to IL-1 beta and interferon-gamma in the presence or absence of 1,25(OH)(2)D-3. Effects on insulin secretion and beta-cell survival were analyzed by glucose-stimulated insulin release and electron microscopy or Hoechst/propidium iodide staining, respectively. Gene expression profiles were assessed by Affymetrix microarrays. Nuclear factor-kappa B activity was tested, whereas effects on secreted chemokines/cytokines were confirmed by ELISA and migration studies. Cytokine exposure caused a significant increase in beta-cell apoptosis, which was almost completely prevented by 1,25(OH)(2)D-3. In addition, 1,25(OH)(2)D-3 restored insulin secretion from cytokine-exposed islets. Microarray analysis of murine islets revealed that the expression of approximately 4000 genes was affected by cytokines after 6 and 24 hours (n = 4; > 1.3-fold; P < .02), of which nearly 250 genes were modified by 1,25(OH)(2)D-3. These genes belong to functional groups involved in immune response, chemotaxis, cell death, and pancreatic beta-cell function/phenotype. In conclusion, these findings demonstrate a direct protective effect of 1,25(OH)(2)D-3 against inflammation-induced beta-cell dysfunction and death in human and murine islets, with, in particular, alterations in chemokine production by the islets. These effects may contribute to the beneficial effects of 1,25(OH)(2)D-3 against the induction of autoimmune diabetes.