Dexamethasone protects human fibroblasts from apoptosis via an S1P3-receptor subtype dependent activation of PKB/Akt and Bcl XL.
Topical used glucocorticoids (GC) represent an important class of steroid hormones for the treatment of a broad range of acute or chronic inflammatory diseases. Most interestingly, GC exert a pronounced anti-apoptotic effect in primary human fibroblasts whereas in variety of hematopoietic cells a pro-apoptotic effect is visible. Recently, it has been discovered that in human fibroblasts the GC dexamethasone (Dex) exerts its protection from programmed cell death via the formation of the lipid mediator sphingosine 1-phosphate (S1P) followed by an activation of the S1P(3)-receptor subtype. In the present study, the molecular mechanism of Dex to protect human fibroblasts from apoptosis was elucidated. Thereupon, Dex not only mediates its anti-apoptotic effect via activation of phosphoinositide 3-kinase (PI3K)/Akt signalling but also includes an involvement of the Bcl-2 family protein Bcl(XL). Most interestingly, the use of S1P(3)-knockout fibroblasts revealed that the S1P(3)-receptor subtype is crucial for activation of PKB/Akt as well as Bcl(XL) by Dex.
Nieuwenhuis
Barbara
B
Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Germany.
Lüth
Anja
A
Kleuser
Burkhard
B
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020011:Protective Agents; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism*
D020011:Protective Agents; D049349:Receptors, Lysosphingolipid; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D053179:Caspase 7