Sphingosine-1-phosphate inhibits nuclear factor kappaB activation and germ cell apoptosis in the human testis independently of its receptors.
Early apoptosis-inducing events are potentially important targets for preventing germ cell loss caused by external stress. The sphingolipid sphingosine-1-phosphate (S1P) is an important regulator of stress-induced apoptosis. It affects the cell as an intracellular signaling molecule or as a ligand to its cell membrane-bound S1P(1-5) receptors. We previously demonstrated that S1P inhibits stress-induced male germ cell death in vitro and in vivo. Here, we further define the mechanisms of S1P-mediated inhibition of male germ cell death. Using immunohistochemistry, we detected expression of the S1P(1) and S1P(2) receptors in the somatic Sertoli cells of the human testis. In a culture of human seminiferous tubules, S1P inhibited germ cell apoptosis, suppressed both nuclear factor kappaB (NF-kappaB) DNA-binding activity and expression of phosphorylated Akt, but did not affect activator protein-1 (AP-1) DNA-binding activity. Dihydro-S1P, which binds to and activates S1P receptors but has no direct intracellular effect, suppressed neither apoptosis nor NF-kappaB activity. These results suggest that S1P inhibits male germ cell apoptosis independently of its receptors, possibly by inhibiting the transcription factor NF-kappaB and Akt phosphorylation.
Suomalainen
Laura
L
Program for Developmental and Reproductive Biology, Hospital for Children and Adolescents, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, 5th floor B529b, P.O. Box 700, FIN-00029, Helsinki, Finland. laura.suomalainen@welho.com
Pentikäinen
Virve
V
Dunkel
Leo
L
D000368:Aged; D017209:Apoptosis; D015139:Blotting, Southern; D015153:Blotting, Western; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005854:Germ Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008024:Ligands; D008246:Lysophospholipids / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D012671:Seminiferous Tubules / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology*; D013737:Testis / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
D020672:I-kappa B Proteins; D008024:Ligands; D008246:Lysophospholipids; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D018808:Transcription Factor AP-1; D000072000:NF-KappaB Inhibitor alpha; C060506:sphingosine 1-phosphate; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases; D013110:Sphingosine
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