RANTES-activated human T lymphocytes. A role for phosphoinositide 3-kinase.
RANTES (regulated on activation, normal T cell expressed and secreted), a member of the chemokine family, is a potent chemoattractant for CD4+/CD45RO human T lymphocytes, but the signal-transduction mechanisms utilized by RANTES are poorly defined. In freshly isolated human T lymphocytes loaded with fura-2 acetoxymethyl, the CD3 mAb, UCHT-1, but not RANTES, elicited elevation of intracellular calcium levels. However, RANTES produced a bell-shaped chemotactic response and an increase in polarization of the T lymphocytes. Immunoprecipitates of phosphoinositide (PI) 3-kinase, derived from T lymphocytes stimulated with RANTES, contained increased in vitro PI 3-kinase activity compared with that present in immunoprecipitates derived from vehicle-treated cells. RANTES induction of PI 3-kinase activity was maximal at 10 to 100 ng/ml. Furthermore, the fungal metabolite, wortmannin, which is a potent PI 3-kinase inhibitor, inhibited RANTES-induced T lymphocyte migration, polarization, and increased PI 3-kinase activity. Our results show that RANTES activation of T lymphocytes seems to be independent of detectable elevation of cytosolic-free calcium, but the functional effects of chemotaxis and polarization, induced by RANTES, seem to involve the putative PI 3-kinase signal-transduction pathway.
Turner
L
L
School of Pharmacy and Pharmacology, University of Bath, United Kingdom.
Ward
S G
SG
Westwick
J
J
D000730:Androstadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5; D002633:Chemotaxis / Q000187:drug effects; D003600:Cytosol / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008222:Lymphokines / Q000494:pharmacology* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D000077191:Wortmannin
D000730:Androstadienes; D018946:Chemokine CCL5; D004791:Enzyme Inhibitors; D008222:Lymphokines; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D002118:Calcium; D000077191:Wortmannin