Sphingosine-1-phosphate inhibits the cytotoxic activity of NK cells via Gs protein-mediated signalling.
Sphingosine-1-phosphate (S1P) is a bioactive phospholipid that transmits signals through G-protein-coupled receptors to control cellular differentiation, survival, and several functions of immune cells. S1P is a chemoattractant for NK cells, which are critical members of the immunological tumor surveillance machinery. In this study we analyzed the influence of S1P on the interaction of NK cells with tumor cells such as the human melanoma cell line Hs294T and the Burkitt's lymphoma cell line Raji. We found that S1P inhibited the cytotoxic activity of NK cells. Analysis of signal transduction pathways revealed that S1P induced common signalling pathways of chemotaxins such as Gi protein-dependent actin reorganization and activation of the phosphatidylinositol 3-kinase (PI3K) dependent signal molecules, protein kinase B (PKB/Akt) and glycogen synthase kinase-3beta (GSK-3beta). In contrast to most chemotaxins, S1P is also able to activate Gs-dependent signalling molecules. This signalling cascade involves increase of cAMP levels and protein kinase A (PKA) activation. Additionally, blocking the regulatory subunits of PKA I abrogated the inhibitory effect of S1P, whereas the catalytic subunits were not involved. Our data indicate that S1P may contributes to the tumor escape from NK cell-dependent immunological surveillance machinery.
Lagadari
Mariana
M
Department of Dermatology, Friedrich-Schiller University, D-07740 Jena, Germany.
Lehmann
Katja
K
Ziemer
Mirjana
M
Truta-Feles
Krisztina
K
Berod
Luciana
L
Idzko
Marco
M
Barz
Dagmar
D
Kamradt
Thomas
T
Maghazachi
Azzam A
AA
Norgauer
Johannes
J
D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015151:Immunoblotting; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D007376:Interleukin-2; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D013110:Sphingosine