Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases

Abstract

We have examined the effect of sphingolipids on the chemotaxis of human natural killer (NK) cells. Messenger RNA for Edg-1, Edg-6 and Edg-8 but not Edg-3, are expressed in these cells. Sphingosine 1 phosphate (SPP), dihydro SPP (DHSPP) or the CC chemokine RANTES (CCL5), but not sphingosine induces the chemotaxis of these cells. Pertussis toxin inhibits the chemotaxis induced by these ligands. Permeabilization of NK cells with streptolysin O (SLO) and introduction of blocking antibodies to the heterotrimeric G proteins, showed that Gαi2, Gαs, Gαq/11 or Gα13 mediate the chemotaxis of SPP, whereas Gαi2, Gαo or Gαq/11 mediate the chemotaxis of DHSPP. Gαi2, Gαo, Gαs, Gαq/11, Gαz or Gα12 mediates RANTES-induced NK cell chemotaxis. Further analysis showed that phosphoinositide 3 kinase (PI3K) inhibitors wortmannin and LY294002 inhibit NK cell chemotaxis induced by SPP, DHSPP or RANTES. Blocking antibody to PI3Kγ inhibits the chemotaxis induced by the three ligands, whereas anti-PI3Kβ was without effect. In contrast, SPP and DHSPP recruit PI3Kβ isozyme into NK cell membranes, suggesting that although this isoform is not involved in chemotaxis, it is activated by these phospholipids.