Lysophosphatidic acid inhibits the cytotoxic activity of NK cells: involvement of Gs protein-mediated signaling.
Lysophosphatidic acid (LPA) is an activator and chemoattractant of NK cells, which are critical members of the immunological tumor surveillance machinery. Here, we analyzed the influence of LPA on the interaction of human NK cells with tumor cells such as the Burkitt lymphoma cell line Raji and the human melanoma cell line A2058. Thereby we found that LPA inhibits the release of perforin and cytotoxic activity of NK cells. Analysis of signal transduction showed that LPA induces common signaling pathways of chemotaxins such as G(i) protein-dependent actin re-organization, activation of the mitogen-activated protein kinase p38 as well as phosphatidylinositol-3-kinase-dependent signal molecules [protein kinase B/Akt and glycogen synthase kinase-3beta (GSK-3beta)]. In contrast to most chemotaxins, LPA is also able to activate G(s)-dependent signaling molecules. This signaling cascade involves the LPA receptor type-2, increase cAMP levels and protein kinase A (PKA) activation, which in turn are responsible for the modulatory effect of LPA on NK cell-mediated cytotoxicity. Moreover, blocking the regulatory subunits of PKA I abrogates the inhibitory effect of LPA, whereas the catalytic subunits are not involved. Based on our data, one can assume that LPA contributes to the tumor escape from the immunological surveillance machinery.
Lagadari
Mariana
M
Department of Dermatology, Friedrich-Schiller University Jena, Erfurterstrasse 35, Jena, Germany.
Truta-Feles
Krisztina
K
Lehmann
Katja
K
Berod
Luciana
L
Ziemer
Mirjana
M
Idzko
Marco
M
Barz
Dagmar
D
Kamradt
Thomas
T
Maghazachi
Azzam A
AA
Norgauer
Johannes
J
D002051:Burkitt Lymphoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000276:immunology / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007157:Immunologic Surveillance; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000276:immunology / Q000378:metabolism*; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D054353:Perforin / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D019139:Tumor Escape; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D054353:Perforin; D019869:Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; C032881:lysophosphatidic acid