1,25-dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the fas receptor

Abstract

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.

Differential expression of prohibitin is correlated with dual action of Vitamin D as a proliferative and antiproliferative hormone in breast epithelial cells

“…In the literature vitamin D is often reported to inhibit both proliferation and apoptosis in cancer cells [9,10]. However the detailed signaling pathway for such dual effects has been poorly understood.…”

Role of Nongenomic Activation of Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathways in 1,25D3-Mediated Apoptosis in Squamous Cell Carcinoma Cells

“…1,25D3 upregulates Bcl-2 protein expression in normal human thyrocytes and protects them from apoptotic cell death (41). 1,25D3 also protects human pancreatic islet cells from tumor necrosis factor/interleukin1h/IFNg-induced apoptosis via the induction of antiapoptotic protein A20 and suppression of Fas expression (42,43). 1,25D3 suppresses death receptor-mediated apoptosis by inhibiting caspase-8 activation and increasing Bcl-2/Bax ratio in human osteoblasts (44).…”

Vitamin D and inflammation in the prevention of type 2 diabetes: public health relevance

“…As reviewed recently by our group [15,16], one of the hallmarks of T2DM is systemic low-grade inflammation, which is characterized by increased serum levels of proinflammatory cytokines and acute phase reactants. In vitro, 1α,25(OH) 2 D protects human islets that are incubated with pro-inflammatory cytokines from apoptosis [45] and modulates the production of the immunostimulatory cytokine IL-12 and the immunosuppressive cytokine IL-10 [46]. Furthermore, VDRs are present in most types of immune cells, thus suggesting a role of vitamin D in the immunity [47].…”