1,25-dihydroxyvitamin D3 protects RINm5F and human islet cells against cytokine-induced apoptosis: implication of the antiapoptotic protein A20.
Transplantation of islets of Langerhans is a potential cure for type 1 diabetes, but its success is hampered by destruction of the islets. The data presented herein suggest that the active metabolite of vitamin D3 [1,25-(OH)2D3] may promote islet cell survival by modulating the effects of inflammatory cytokines, which contribute to beta-cell demise. We investigated some of the mechanisms triggering the apoptotic machinery in rat insulinoma RINm5F cells and human islets treated with IL-1beta plus interferon-gamma plus TNFalpha and assessed the effects of 1,25-(OH)2D3 in these processes. Mitochondrial transmembrane permeability and apoptotic features, determined by percentage of sub-G1 cells, quantitation of DNA strand breaks, and Hoechst staining, were significantly increased by cytokines and reverted toward control values by 1,25-(OH)2D3 cotreatment. The cytoprotection of cells correlated with the abrogation of cytokine-induced nitric oxide production. The activation of nuclear factor-kappaB plays a key role in the different pathways implicated in nitric oxide generation. We demonstrated for the first time, in both RINm5F cells and human islets, that 1,25-(OH)2D3 was able to induce and maintain high levels of A20, an antiapoptotic protein known to block nuclear factor-kappaB activation. Our study showed a clear efficiency of 1,25-(OH)2D3 on the apoptotic machinery triggered by cytokines in beta-cells and suggests that 1,25-(OH)2D3 could help overcome a major obstacle encountered in the cellular therapy of diabetes, such as nonfunction in the immediate posttransplantation period.
Riachy
Rita
R
Cellular Therapy of Diabetes, Institut National de la Santé et de la Recherche Médicale, Equipe de Recherche et d'Innovation Méthodologique 0106, Faculté de Médecine, 59045 Lille, France.
Vandewalle
Brigitte
B
Kerr Conte
Julie
J
Moerman
Ericka
E
Sacchetti
Paola
P
Lukowiak
Bruno
B
Gmyr
Valery
V
Bouckenooghe
Thomas
T
Dubois
Mathilde
M
Pattou
François
F
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002117:Calcitriol / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D053938:DNA Fragmentation / Q000187:drug effects; D004268:DNA-Binding Proteins; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase; D007150:Immunohistochemistry; D007340:Insulinoma / Q000473:pathology*; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000648:ultrastructure*; D008928:Mitochondria / Q000648:ultrastructure; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins; D010190:Pancreatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D014407:Tumor Cells, Cultured; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002843:Chromatin; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D002117:Calcitriol