Lagadari Mariana, Lehmann Katja, Ziemer Mirjana, Truta-Feles Krisztina, Berod Luciana, Idzko Marco, Barz Dagmar, Kamradt Thomas, Maghazachi Azzam A, Norgauer Johannes
Department of Dermatology, Friedrich-Schiller University, D-07740 Jena, Germany.
Int J Oncol. 2009 Jan;34(1):287-94.
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.
鞘氨醇-1-磷酸（S1P）是一种生物活性磷脂，它通过G蛋白偶联受体传递信号，以控制细胞分化、存活以及免疫细胞的多种功能。S1P是自然杀伤细胞（NK细胞）的趋化因子，NK细胞是免疫肿瘤监测机制的关键成员。在本研究中，我们分析了S1P对NK细胞与肿瘤细胞（如人黑色素瘤细胞系Hs294T和伯基特淋巴瘤细胞系Raji）相互作用的影响。我们发现S1P抑制了NK细胞的细胞毒性活性。信号转导通路分析显示，S1P诱导了趋化因子的常见信号通路，如Gi蛋白依赖性肌动蛋白重组以及磷脂酰肌醇3激酶（PI3K）依赖性信号分子、蛋白激酶B（PKB/Akt）和糖原合酶激酶-3β（GSK-3β）的激活。与大多数趋化因子不同，S1P还能够激活Gs依赖性信号分子。这种信号级联反应涉及cAMP水平的升高和蛋白激酶A（PKA）的激活。此外，阻断PKA I的调节亚基可消除S1P的抑制作用，而催化亚基则不参与其中。我们的数据表明，S1P可能有助于肿瘤逃避NK细胞依赖性免疫监测机制。
