Leucocyte chemotaxis: Examination of mitogen-activated protein kinase and phosphoinositide 3-kinase activation by Monocyte Chemoattractant Proteins-1, -2, -3 and -4.
Monocyte Chemoattractant Proteins (MCPs) form a distinct, structurally-related subclass of CC chemokines. They are major chemoattractants for monocytes and T lymphocytes. The MCPs bind to specific G-protein-coupled receptors, initiating a signal cascade within the cell. Though the signal transduction pathways involved in MCP-1-mediated chemotaxis have been studied, the signalling pathways through which MCP-2, -3 and -4 trigger cell migration are not established. In this study, we examined the mitogen-activated protein kinase (MAPK) activation elicited by the MCPs (1-4) and its specific role in chemotaxis. Within 2 min, the MCPs (1-4) elicited a rapid and transient activation of MAPK in peripheral blood mononuclear cells and in HEK-293 cells expressing CCR2b. U0126, an inhibitor of MAPK-kinase (MEK) activation, not only prevented extracellular signal-regulated kinase 1/2 (ERK1/2) activation but also significantly inhibited the MCP-mediated chemotaxis. PI3K inhibitors Wortmannin and LY294002 also partially inhibited the MCP-induced chemotaxis. However, these compounds did not significantly inhibit ERK1/2 activation. As PI3K inhibitors partially inhibit the MCP-mediated chemotaxis but do not significantly effect ERK1/2 activation, these data suggest that co-ordinated action of distinct signal pathways is required to produce chemokine-mediated chemotaxis.
Wain
J H
JH
The Applied Immunobiology Group, Department of Surgery, The Medical School, University of Newcastle Upon Tyne, UK.
Kirby
J A
JA
Ali
S
S
D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology; D054410:Chemokine CCL7; D054412:Chemokine CCL8; D002634:Chemotaxis, Leukocyte; D016207:Cytokines; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018945:Monocyte Chemoattractant Proteins / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D018932:Chemokine CCL2; D054410:Chemokine CCL7; D054412:Chemokine CCL8; D016207:Cytokines; D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D018945:Monocyte Chemoattractant Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C099677:CCL13 protein, human; C515450:CCL7 protein, human; C515453:CCL8 protein, human; C515334:CCR2 protein, human