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International Immunology Advance Access originally published online on May 21, 2009
International Immunology 2009 21(6):667-677; doi:10.1093/intimm/dxp035
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© The Japanese Society for Immunology. 2009. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Lysophosphatidic acid inhibits the cytotoxic activity of NK cells: involvement of Gs protein-mediated signaling

Mariana Lagadari1, Krisztina Truta-Feles1, Katja Lehmann1, Luciana Berod1, Mirjana Ziemer1, Marco Idzko2, Dagmar Barz3, Thomas Kamradt4, Azzam A. Maghazachi5 and Johannes Norgauer1

1 Department of Dermatology, Friedrich-Schiller University Jena, Erfurterstrasse 35, D-07740 Jena, Germany
2 Department of Pneumology, Albert-Ludwigs University, Freiburg, Germany
3 Institute of Transfusion Medicine, Friedrich-Schiller University Jena, Jena, Germany
4 Institute of Immunology, Friedrich-Schiller University Jena, Jena, Germany
5 Department of Physiology, University of Oslo, Oslo, Norway

Correspondence to: J. Norgauer; E-mail: johannes.norgauer{at}med.uni-jena.de

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 Gi 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-3β (GSK-3β)]. In contrast to most chemotaxins, LPA is also able to activate Gs-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.

Keywords: cytotoxicity, lipid mediators

Transmitting editor: M. Reth

Received 3 July 2008, accepted 16 March 2009.


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