Involvement of the ABC-transporter ABCC1 and the sphingosine 1-phosphate receptor subtype S1P(3) in the cytoprotection of human fibroblasts by the glucocorticoid dexamethasone.
Glucocorticoids (GC) represent the most commonly used drugs for the treatment of acute and chronic inflammatory skin diseases. However, the topical long-term therapy of GC is limited by the occurrence of skin atrophy. Most interestingly, although GC inhibit proliferation of human fibroblasts, they exert a pronounced anti-apoptopic action. In the present study, we further elucidated the molecular mechanism of the GC dexamethasone (Dex) to protect human fibroblasts from programmed cell death. Dex not only significantly alters the expression of the cytosolic isoenzyme sphingosine kinase 1 but also initiated an enhanced intracellular formation of the sphingolipid sphingosine 1-phosphate (S1P). Investigations using S1P (3) ((-/-)) -fibroblasts revealed that this S1P-receptor subtype is essential for the Dex-induced cytoprotection. Moreover, we demonstrate that the ATP-binding cassette (ABC)-transporter ABCC1 is upregulated by Dex and may represent a crucial carrier to transport S1P from the cytosol to the S1P(3)-receptor subtype.
Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Germany.
Barbara
B
Nieuwenhuis
Anja
A
Lüth
Jerold
J
Chun
Andrea
A
Huwiler
Josef
J
Pfeilschifter
Monika
M
Schäfer-Korting
Burkhard
B
Kleuser
D017209:Apoptosis; D002478:Cells, Cultured; D019610:Cytoprotection; D003907:Dexamethasone / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*
D003907:Dexamethasone; D005938:Glucocorticoids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D049349:Receptors, Lysosphingolipid; C421109:multidrug resistance-associated protein 1