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1,25-Dihydroxyvitamin D3 Modulates Expression of Chemokines and Cytokines in Pancreatic Islets: Implications for Prevention of Diabetes in Nonobese Diabetic Mice

Laboratory of Experimental Medicine and Endocrinology (C.A.G., H.C., A.G., R.B., C.M.) and Laboratory for Clinical Chemistry (L.H.), Katholieke Universiteit Leuven, 3000 Leuven, Belgium; and Laboratory of Experimental Medicine (A.K.C., D.L.E.), Université Libre de Bruxelles, 1070 Brussels, Belgium

Address all correspondence and requests for reprints to: Chantal Mathieu, M.D., Ph.D., Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: chantal.mathieu{at}med.kuleuven.ac.be.

1,25-Dihydroxyvitamin D₃ (1,25-(OH)₂D₃) is an immune modulator that prevents experimental autoimmune diseases. Receptors for 1,25-(OH)₂D₃ are present in pancreatic ß-cells, the target of an autoimmune assault in nonobese diabetic (NOD) mice. The aim of this study was to investigate the in vivo and in vitro effects of 1,25-(OH)₂D₃ on ß-cell gene expression and death and correlate these findings to in vivo diabetes development in NOD mice. When female NOD mice were treated with 1,25-(OH)₂D₃ (5 µg/kg per 2 d), there was a decrease in islet cytokine and chemokine expression, which was accompanied by less insulitis. Complementing these findings, we observed that exposure to 1,25-(OH)₂D₃ in three cell systems INS-1^E cell line, fluorescence-activated cell sorting purified rat ß-cells, and NOD-severe combined immunodeficient islets) suppressed IP-10 and IL-15 expression in the ß-cell itself but did not prevent cytokine-induced ß-cell death. This 1,25-(OH)₂D₃-induced inhibition of chemokine expression in ß-cells was associated with a decreased diabetes incidence in some treatment windows targeting early insulitis. Thus, although a short and early intervention with 1,25-(OH)₂D₃ (3–14 wk of age) reduced diabetes incidence (35 vs. 58%, P 0.05), a late intervention (from 14 wk of age, when insulitis is present) failed to prevent disease. Of note, only early and long-term treatment (3–28 wk of age) prevented disease to a major extent (more than 30% decrease in diabetes incidence). We conclude that 1,25-(OH)₂D₃ monotherapy is most effective in preventing diabetes in NOD mice when applied early. This beneficial effect of 1,25-(OH)₂D₃ is associated with decreased chemokine and cytokine expression by the pancreatic islets.

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