1,25-dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: Implications for prevention of diabetes in nonobese diabetic mice

1,25- Dihydroxyvitamin D-3 ( 1,25-( OH)(2)D-3) is an immune modulator that prevents experimental autoimmune diseases. Receptors for 1,25-( OH)(2)D-3 are present in pancreatic beta- 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)(2)D-3 on beta- 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)(2)D-3 ( 5 mu g/ 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)(2)D-3 in three cell systems INS-1(E) cell line, fluorescence- activated cell sorting purified rat beta- cells, and NOD- severe combined immunodeficient islets) suppressed IP- 10 and IL- 15 expression in the beta- cell itself but did not prevent cytokine- induced beta- cell death. This 1,25( OH) D-2(3)- induced inhibition of chemokine expression in beta- 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)(2)D-3 ( 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)(2)D-3 monotherapy is most effective in preventing diabetes in NOD mice when applied early. This beneficial effect of 1,25-( OH)(2)D-3 is associated with decreased chemokine and cytokine expression by the pancreatic islets.