Beneficial effect of 1,25 dihydroxyvitamin D-3 on cytokine-treated human pancreatic islets

We examined whether 1,35 dihydroxyvitamin D-3 (1,25 D-3), the active form o f vitamin D involved in the regulation of the immune system, may also prote ct human pancreatic islet cells from destruction induced by cytokines. III this study, we specifically investigated the effect of 1,25 D, oil oxidativ e stress and major histocompatibility complex (MHC) induction, both implica ted ill cytokine-induced islet cell dysfunction and destruction. We also in vestigated the effects of 1,25 D, on interleukin (IL)-6, a pleiotropic cyto kine implicated in the pathogenesis of immunoinflammatory disorders. Human pancreatic islets, isolated from heart-beating donors, were treated w ith a combination of three cytokines, IL-1 beta +tumor necrosis factor alph a +interferon gamma, in the presence or absence of vitamin D, and compared with with untreated control cells. Metabolic activity was assessed by cell viability and insulin content. Oxidative stress was estimated by heat shock protein 70 (hsp70) expression, cell manganese superoxide dismutase (MnSOD) activity and nitrite release, a reflexion of nitric oxide (NO) synthesis. Variation of immunogenicity of islet preparations was determined by analysi s of the MHC class I and class II transcripts. Inflammatory status was eval uated by IL-G production. After 48 h of contact with cytokines, insulin con tent was significantly decreased by 40% but cell viability was not altered. MHC expression significantly increased six- to sevenfold as well as NO and IL-6 release (two- to threefold enhancement). MnSOD activity was not signi ficantly induced and hsp70 expression was not affected by the combination o f cytokines. The addition of 1,25 D-3 significantly reduced nitrite release, IL-6 produc tion and MHC class I expression which then became not significantly differe nt from controls. These results suggest that the effect of 1,25 D-3 in huma n pancreatic islets cells may be a reduction of the vulnerability of cells to cytotoxic T lymphocytes and a reduction of cytotoxic challenge. Hence, 1 ,25 D-3 might play a role in the prevention of type 1 diabetes and islet al lograft rejection.