title: Discovery of molecular pathways mediating 1,25-dihydroxyvitamin D3 protection against cytokine-induced inflammation and damage of human and male mouse islets of Langerhans.
abstract: Protection against insulitis and diabetes by active vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), in nonobese diabetic mice has until now mainly been attributed to its immunomodulatory effects, but also protective effects of this hormone on inflammation-induced β-cell death have been reported. The aim of this study was to clarify the molecular mechanisms by which 1,25(OH)2D3 contributes to β-cell protection against cytokine-induced β-cell dysfunction and death. Human and mouse islets were exposed to IL-1β and interferon-γ in the presence or absence of 1,25(OH)2D3. Effects on insulin secretion and β-cell survival were analyzed by glucose-stimulated insulin release and electron microscopy or Hoechst/propidium iodide staining, respectively. Gene expression profiles were assessed by Affymetrix microarrays. Nuclear factor-κB activity was tested, whereas effects on secreted chemokines/cytokines were confirmed by ELISA and migration studies. Cytokine exposure caused a significant increase in β-cell apoptosis, which was almost completely prevented by 1,25(OH)2D3. In addition, 1,25(OH)2D3 restored insulin secretion from cytokine-exposed islets. Microarray analysis of murine islets revealed that the expression of approximately 4000 genes was affected by cytokines after 6 and 24 hours (n = 4; >1.3-fold; P < .02), of which nearly 250 genes were modified by 1,25(OH)2D3. These genes belong to functional groups involved in immune response, chemotaxis, cell death, and pancreatic β-cell function/phenotype. In conclusion, these findings demonstrate a direct protective effect of 1,25(OH)2D3 against inflammation-induced β-cell dysfunction and death in human and murine islets, with, in particular, alterations in chemokine production by the islets. These effects may contribute to the beneficial effects of 1,25(OH)2D3 against the induction of autoimmune diabetes.
authors.affiliation: Clinical and Experimental Endocrinology (H.W.-K., D.R., H.K., L.O., C.M.), University Hospital Gasthuisberg, Gene Expression Unit (L.V.L., F.S.), Department of Molecular and Cellular Medicine, Department of Microbiology and Immunology (P.P.), B-3000 Leuven, Belgium; Hans Christian Andersen Children's Hospital (H.W.-K., H.T.C.) and Department of Clinical Genetics (K.B., D.L.E.), Odense University Hospital, DK-5000, Odense, Denmark; Department of Endocrinology and Metabolism (M.B., P.M.), Metabolic Unit, and Department of General Pathology (M.M.), University of Pisa, Pisa, Italy; and Laboratory of Experimental Medicine (D.L.E.), Université Libre de Bruxelles, B-1070 Brussels, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Wolden-Kirk
authors.forename: D
authors.initials: D
authors.lastname: Rondas
authors.forename: M
authors.initials: M
authors.lastname: Bugliani
authors.forename: H
authors.initials: H
authors.lastname: Korf
authors.forename: L
authors.initials: L
authors.lastname: Van Lommel
authors.forename: K
authors.initials: K
authors.lastname: Brusgaard
authors.forename: H T
authors.initials: HT
authors.lastname: Christesen
authors.forename: F
authors.initials: F
authors.lastname: Schuit
authors.forename: P
authors.initials: P
authors.lastname: Proost
authors.forename: M
authors.initials: M
authors.lastname: Masini
authors.forename: P
authors.initials: P
authors.lastname: Marchetti
authors.forename: D L
authors.initials: DL
authors.lastname: Eizirik
authors.forename: L
authors.initials: L
authors.lastname: Overbergh
authors.forename: C
authors.initials: C
authors.lastname: Mathieu
mesh_terms: D000368:Aged; D000818:Animals; D002117:Calcitriol / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002478:Cells, Cultured; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D007371:Interferon-gamma; D002117:Calcitriol; D005947:Glucose