1,25-Dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the Fas receptor.
Beta cell loss occurs at the onset of type 1 diabetes and after islet graft. It results from the dysfunction and destruction of beta cells mainly achieved by apoptosis. One of the mediators believed to be involved in beta cell apoptosis is Fas, a transmembrane cell surface receptor transducing an apoptotic death signal and contributing to the pathogenesis of several autoimmune diseases. Fas expression is particularly induced in beta cells by inflammatory cytokines secreted by islet-infiltrating mononuclear cells and makes cells susceptible to apoptosis by interaction with Fas-ligand expressing cells. We have previously demonstrated that 1,25(OH)2D3, the active metabolite of vitamin D, known to exhibit immunomodulatory properties and prevent the development of type 1 diabetes in NOD mice, is efficient against apoptosis induced by cytokines in human pancreatic islets in vitro. The effects were mainly mediated by the inactivation of NF-kappa-B. In this study we demonstrated that 1,25(OH)2D3 was also able to counteract cytokine-induced Fas expression in human islets both at the mRNA and protein levels. These results were reinforced by our microarray analysis highlighting the beneficial effects of 1,25(OH)2D3 on death signals induced by Fas activation. Our results provides additional evidence that 1,25(OH)2D3 may be an interesting tool to help prevent the onset of type 1 diabetes and improve islet graft survival.
Riachy
R
R
Faculté de Médecine, Cellular Therapy of Diabetes, Institut National de la Santé et de la Recherche Médicale, ERIT-M 0106, 59045, Lille, France.
Vandewalle
B
B
Moerman
E
E
Belaich
S
S
Lukowiak
B
B
Gmyr
V
V
Muharram
G
G
Kerr Conte
J
J
Pattou
F
F
D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D002117:Calcitriol / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects*; D009924:Organ Culture Techniques; D010179:Pancreas / Q000166:cytology; D020011:Protective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D016207:Cytokines; D020011:Protective Agents; D012333:RNA, Messenger; D019014:fas Receptor; D002117:Calcitriol