Activation of phosphoinositide 3-kinases by the CCR4 ligand macrophage-derived chemokine is a dispensable signal for T lymphocyte chemotaxis.
Macrophage-derived chemokine (MDC/CC chemokine ligand 22 (CCL22)) mediates its cellular effects principally by binding to its receptor CCR4, and together they constitute a multifunctional chemokine/receptor system with homeostatic and inflammatory roles in the body. We report the CCL22-induced accumulation of phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P(3)) in the leukemic T cell line CEM. CCL22 also had the ability to chemoattract human Th2 cells and CEM cells in a pertussis toxin-sensitive manner. Although the PI(3,4,5)P(3) accumulation along with the pertussis toxin-susceptible phosphorylation of protein kinase B were sensitive to the two phosphoinositide 3-kinase inhibitors, LY294002 and wortmannin, cell migration was unaffected. However, cell migration was abrogated with the Rho-dependent kinase inhibitor, Y-27632. These data demonstrate that although there is PI(3,4,5)P(3) accumulation downstream of CCR4, phosphoinositide 3-kinase activity is a dispensable signal for CCR4-stimulated chemotaxis of Th2 cells and the CEM T cell line.
Cronshaw
Darran G
DG
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
Owen
Charles
C
Brown
Zarin
Z
Ward
Stephen G
SG
D045744:Cell Line, Tumor; D002478:Cells, Cultured; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology; D054460:rho-Associated Kinases
D054422:Chemokine CCL22; D019742:Chemokines, CC; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D054460:rho-Associated Kinases; C515482:CCL22 protein, human; C515354:CCR4 protein, human; C060974:phosphatidylinositol 3,4,5-triphosphate