Role of Lysophospholipids in the Biological Activity of NK Cells

LAGADARI MARIANA

Friedrich-Schiller-Universitat_Jena

Lugar: Jena; Año: 2008 p. 214

Lysophosphatidic acid and sphingosine 1-phosphate are bioactive lysophospholipids (LPLs) that transmit signals through a family of G-protein-couple receptors to control cellular differentiation and survival, as well as vital function of several types of immune cells. In addition, LPA and S1P are potent inducers of many of the hallmarks of cancer including cell proliferation, survival, migration, invasion and neovascularization. The enzymes that produce these two small lysophospholipids are aberrant in multiple cancer lineages and exhibit transforming activity. Additionally, LPLs levels are increased in patients with several types of cancer including melanoma. NK cells are critical members of the immunological tumor surveillance machinery. They are able to attack abnormal cells such as virus-infected cells or transformed tumor cells. Enhanced NK cell cytotoxic activity after stimulation with classical chemotaxins such as RANTES/CCL5 is well known. These classical chemotaxins bind to specific Gi protein-coupled receptors linked to activation of phospholipase C and PIP3?generating type IB phosphatidylinositol 3-kinase. Moreover, LPA and S1P induce chemotaxis of NK cells through pertussis toxin sensitive-G proteins. In this context, the biological functions of LPLs and their influence on the interaction of human NK cells with tumor cells were characterized. The results presented in this work indicate that LPA and S1P in contrast to classical chemotaxins such as CC chemokines stimulate Gi as well Gs protein-dependent signalling pathways in NK cell. While LPL-induced actin polymerization is dependent on Gi activation, LPL activation of NK cells results in increased cAMP levels and decreased cytotoxic activity against tumor cells. Consequently, cAMP signalling leads to the immediate activation of protein kinase A. Moreover, blocking the regulatory subunits of PKA I abrogates the inhibitory effect of LPLs, whereas the catalytic subunits are not involved. The inhibitory effect of LPLs on NK cell cytotoxicity have been observed with Burkitt´s lymphoma cell line Raji and the A2058, HS294T and SK-Mel 23 human melanoma cell lines and at various effector:target ratios. Therefore one can assume that activities of NK cells are impaired in vivo by local production of LPLs. LPA and S1P may block the activity of a major anti-tumor effector cells i.e. NK cells, providing a favourable environment for the growth of tumor cells.