title: 1Alpha,25-dihydroxyvitamin D3 protects human keratinocytes from apoptosis by the formation of sphingosine-1-phosphate.
abstract: Owing to its ability to induce growth arrest and differentiation of keratinocytes, 1alpha,25-dihydroxyvitamin D3 and its analogs are useful for the treatment of hyperproliferative skin diseases, such as psoriasis vulgaris. It has been implicated that the 1alpha,25-dihydroxyvitamin D3-induced differentiation of keratinocytes is mediated, at least in part, by the formation of ceramides; however, ceramides have also been identified to induce apoptosis in many cells, including keratinocytes. Therefore, it was of interest to investigate the influence of 1alpha,25-dihydroxyvitamin D3 on apoptosis in keratinocytes. Most interestingly, physiological concentrations of 1alpha,25-dihydroxyvitamin D3 did not induce apoptosis in keratinocytes, despite the formation of ceramides. Moreover, 1alpha,25-dihydroxyvitamin D3 appeared cytoprotective and made keratinocytes resistant to apoptosis induced by ceramides, ultraviolet irradiation, or tumor necrosis factor-alpha. The cytoprotective effect was accompanied by the formation of the sphingolipid breakdown product sphingosine-1-phosphate, which prevented apoptosis in analogy to 1alpha,25-dihydroxyvitamin D3. The effect of 1alpha,25-dihydroxyvitamin D3 was specific as the almost inactive precursor cholecalciferol neither induced sphingosine-1-phosphate formation nor prevented cells from apoptosis. Besides this, the cytoprotective aptitude of 1alpha,25-dihydroxyvitamin D3 was completely abolished by the sphingosine kinase inhibitor N,N-dimethylsphingosine, which blocked sphingosine-1-phosphate formation. Moreover, sphingosine-1-phosphate was able to restore the cytoprotective effect of 1alpha,25-dihydroxyvitamin D3 in the presence of N,N-dimethylsphingosine. Taken together, here we report for the first time that 1alpha,25-dihydroxyvitamin D3 protects keratinocytes from apoptosis and additionally this cytoprotection is mediated via the formation of sphingosine-1-phosphate.
authors.affiliation: Institut für Pharmazie, Abteilung für Pharmakologie, Freie Universität Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Manggau
authors.forename: D S
authors.initials: DS
authors.lastname: Kim
authors.forename: L
authors.initials: L
authors.lastname: Ruwisch
authors.forename: R
authors.initials: R
authors.lastname: Vogler
authors.forename: H C
authors.initials: HC
authors.lastname: Korting
authors.forename: M
authors.initials: M
authors.lastname: Schäfer-Korting
authors.forename: B
authors.initials: B
authors.lastname: Kleuser
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism / Q000494:pharmacology; D019610:Cytoprotection; D006801:Humans; D006887:Hydroxycholecalciferols; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000473:pathology / Q000502:physiology* / Q000528:radiation effects; D008246:Lysophospholipids; D009336:Necrosis; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000494:pharmacology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014466:Ultraviolet Rays; D000099157:Sphingosine Kinase
chemical_list: D002117:Calcitriol; D002518:Ceramides; D006887:Hydroxycholecalciferols; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D019253:Proto-Oncogene Proteins c-bcl-2; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C061800:N,N-dimethylsphingosine; C008088:alfacalcidol