Sphingosine-1-phosphate and its potentially paradoxical effects on critical parameters of cutaneous wound healing.
The sphingolipid metabolite sphingosine-1-phosphate has emerged as a new bioactive molecule involved in the regulation of cell growth, differentiation, survival, and chemotaxis as well as angiogenesis and embryogenesis. These effects are mediated either via G-protein-coupled receptors or through intracellular actions. The most prominent sources of sphingosine-1-phosphate are human platelets suggesting its potential role in wound healing. In agreement with a positive function on reconstruction of wounded skin, we identified sphingosine-1-phosphate as a potent chemoattractant for keratinocytes as well as an activator of extracellular matrix production by fibroblasts. An unexpected finding is a strong cell growth arrest of keratinocytes after exposure to sphingosine-1-phosphate, as keratinocyte proliferation is critical for re-epithelialization of the wound. Most interestingly, the anti-proliferative effect of sphingosine-1-phosphate is not a result of cytotoxicity or apoptosis as sphingosine-1-phosphate even protects these cells from programmed cell death. Moreover, sphingosine-1-phosphate enhances differentiation of keratinocytes. To investigate further by which signaling pathway cell growth inhibition is mediated expression of the mRNA of all sphingosine-1-phosphate receptors (S1P1-5) was identified. 1 (Edg 1), 2 (Edg 5), 3 (Edg 3), 4 (Edg 6), and 5 (Edg 8) mRNA in keratinocytes was identified. As demonstrated in guanosine 5-[gamma-35S] triphosphate-gammaS binding assays, these G-protein-coupled receptors are functional at nanomolar concentrations. As the anti-proliferative effect of sphingosine-1-phosphate is only partially inhibited in the presence of pertussis toxin, it was investigated if intracellular actions are also involved. Microinjections of sphingosine-1-phosphate in keratinocytes also reduce proliferation suggesting that both sphingosine-1-phosphate receptors as well as intracellular actions mediate sphingosine-1-phosphate- induced cell growth arrest.
Vogler
Rüdiger
R
Institute of Pharmacy, Pharmacology and Toxicology, Free University of Berlin, Königin-Luise-Str. 2+4, Germany.
Sauer
Bettina
B
Kim
Dong-Seok
DS
Schäfer-Korting
Monika
M
Kleuser
Burkhard
B
D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D008246:Lysophospholipids; D008845:Microinjections; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000235:genetics* / Q000494:pharmacology*; D013462:Sulfur Radioisotopes; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
D008246:Lysophospholipids; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D013462:Sulfur Radioisotopes; C060506:sphingosine 1-phosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013110:Sphingosine