Glucocorticoids mediate differential anti-apoptotic effects in human fibroblasts and keratinocytes via sphingosine-1-phosphate formation.
Glucocorticoids are potent anti-inflammatory and immunomodulatory drugs which also induce growth inhibition in a variety of cell types. For this reason long-term treatment of inflammatory skin diseases may result in irreversible skin atrophy. To elucidate whether the antiproliferative action of glucocorticoids in fibroblasts is accompanied by induction of apoptosis we investigated the influence of dexamethasone (DEX) on both parameters. Interestingly, we revealed that growth inhibitory concentrations of this glucocorticoid did not induce fibroblast apoptosis. Moreover, DEX protected these cells from apoptosis induced by tumor necrosis factor alpha (TNFalpha)/actinomycin, UV-irradiation, and cell permeable ceramides. These findings are in contrast to the lack of anti-apoptotic effects detected in keratinocytes. Although DEX inhibited TNFalpha mediated nuclear factor-kappa (NF-kappaB) activity in fibroblasts, this mechanism was not involved in its cytoprotection as it was verified by specific NF-kappaB inhibitors. Therefore, we looked for alternative intracellular mediators. Coincubation of fibroblasts with the sphingosine kinase inhibitor N,N-dimethylsphingosine, which blocks formation of the sphingolipid degradation product sphingosine-1-phosphate (S1P), abrogated the protective glucocorticoid effect almost completely. As preincubation with S1P reduced the number of apoptotic cells after stimulation with TNFalpha/actinomycin and moreover DEX increased the intracellular S1P content a role of this sphingolipid in the cytoprotection by DEX is suggested.
Hammer
S
S
Institut für Pharmazie, Abteilung für Pharmakologie und Toxikologie, Freie Universität Berlin, Berlin, Germany.
Sauer
B
B
Spika
I
I
Schraut
C
C
Kleuser
B
B
Schäfer-Korting
M
M
D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008156:Luciferases; D008246:Lysophospholipids / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D005938:Glucocorticoids; D008246:Lysophospholipids; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C060506:sphingosine 1-phosphate; D003907:Dexamethasone; D008156:Luciferases; D013110:Sphingosine