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 microg/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)(2)D(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 < or = 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.
Gysemans
Conny A
CA
Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium.
Cardozo
Alessandra K
AK
Callewaert
Hanne
H
Giulietti
Annapaula
A
Hulshagen
Leen
L
Bouillon
Roger
R
Eizirik
Décio L
DL
Mathieu
Chantal
C
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology* / Q000627:therapeutic use; D018925:Chemokines / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD
D018925:Chemokines; D016207:Cytokines; D007375:Interleukin-1; D007371:Interferon-gamma; D002117:Calcitriol