Signal transduction involved in MCP-1-mediated monocytic transendothelial migration.
Monocyte chemoattractant protein-1 (MCP-1) is a major chemoattractant for monocytes and T lymphocytes. The MonoMac6 cell line was used to examine MCP-1 receptor-mediated signal transduction events in relation to MCP-1-mediated monocytic transendothelial migration. MCP-1 stimulates, with distinct time courses, extracellular signal-related kinases (ERK1 and ERK2) and stress-activated protein kinases (SAPK1/JNK1 and SAPK2/p38). SAPK1/JNK1 activation was blocked by piceatannol, indicating that it is regulated by Syk kinase, whereas SAPK2/p38 activation was inhibited by PP2, revealing an upstream regulation by Src-like kinases. In contrast, ERK activation was insensitive to PP2 and piceatannol. Pertussis toxin, a blocker of Go/Gi proteins, abrogated MCP-1-induced ERK activation, but was without any effect on SAPK1/JNK1 and SAPK2/p38 activation. These results underscore the major implication of Go/Gi proteins and nonreceptor tyrosine kinases in the early MCP-1 signaling. Furthermore, MCP-1-mediated chemotaxis and transendothelial migration were significantly diminished by a high concentration of SB202190, a broad SAPK inhibitor, or by SB203580, a specific inhibitor of SAPK2/p38, and abolished by pertussis toxin treatment. Altogether, these data suggest that coordinated action of distinct signal pathways is required to produce a full response to MCP-1 in terms of monocytic locomotion.
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INSERM U364, Faculté de Médecine, Nice, France.
Pomeranz
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Millet
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Rossi
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Schmid-Alliana
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D002460:Cell Line; D018932:Chemokine CCL2 / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072377:Syk Kinase; D014470:Umbilical Cord / Q000166:cytology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D005353:Fibronectins; D047908:Intracellular Signaling Peptides and Proteins; D010566:Virulence Factors, Bordetella; D002772:Cholera Toxin; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases