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 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.

1,25-Dihydroxyvitamin D3 Selectively Modulates Tolerogenic Properties in Myeloid but Not Plasmacytoid Dendritic Cells

“…Multiple mechanisms contribute to induction of DC tolerogenicity by VDR agonists, from down-regulation of costimulatory molecules, both membrane-bound as CD40, CD80, CD86 and secreted as IL-12, to up-regulation of anti-inflammatory molecules like 25). Additional mechanisms involve modulation of chemokine secretion, enhancing the production of chemokines able to recruit regulatory/suppressor T cells, and inhibiting chemokine production by target organs in autoimmune diseases (26,27). These effects are not limited to in vitro activity: 1,25(OH) 2 D 3 and its analogs can also induce DCs with tolerogenic properties in vivo, as demonstrated in models of allograft rejection (28,29).…”

Vitamin D and diabetes

“…Moreover, it was reported that 1,25(OH) 2 D 3 induced and maintained high levels of A20, an anti-apoptotic protein, in rat RINm5F cells and human islets after exposure to inflammatory cytokines [86]. We recently performed a comparative study of different cell systems (whole rat islets, FACS-purified beta cells and INS-1E cells) and did not observe direct protection by 1,25(OH) 2 D 3 against cytokine-induced beta cell death, but demonstrated decreased expression of chemokines by beta cells treated with 1,25(OH) 2 D 3 [87].…”

1,25-Dihydroxyvitamin D3 inhibits proliferation but not the suppressive function of regulatory T cells in the absence of antigen-presenting cells

“…4,5 A role for vitamin D 3 in immune regulation has been demonstrated both in vivo and in vitro; 1,25(OH) 2 D 3 influences the growth, differentiation and cytokine production of various immune cells. [6][7][8] As a result, 1,25(OH) 2 D 3 has been proposed as a potential immunomodulatory agent in autoimmune diseases such as insulin-dependent diabetes mellitus, multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis, [9][10][11] as well as in cancer 12 and infectious diseases such as HIV infection. 13 Regulatory T (Treg) cells are characterized by a CD4 + CD25 high phenotype and signature transcription factor, forkhead box protein 3 (Foxp3).…”