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

Abstract

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 β-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 β-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 β-cells, and NOD-severe combined immunodeficient islets) suppressed IP-10 and EL-15 expression in the β-cell itself but did not prevent cytokine-induced β-cell death. This 1,25-(OH)2D 3-induced inhibition of chemokine expression in β-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. Copyright © 2005 by The Endocrine Society.