title: Monocyte chemoattractant protein-1-induced activation of p42/44 MAPK and c-Jun in murine peritoneal macrophages: a potential pathway for macrophage activation.
abstract: The role of monocyte chemoattractant protein-1 (MCP-1) in mediating the infiltration and activation of monocytes/macrophages into the sites of inflammation or tumor growth is well documented, but the molecular mechanism(s) involved in the process is poorly understood. In the current investigation, we demonstrate activation of the p42/44 MAPK-mediated signal transduction in murine peritoneal macrophages on stimulation with MCP-1 (10-100 ng/ml) in vitro. The p42/44 MAPK activation was determined by studying the expression of the phosphorylated p42/44 MAPK (Thr202/Tyr204) in the MCP-1-treated macrophages. This response was found to be rapid and time dependent, detectable within 5 min of MCP-1 stimulation. PD98058 (5-50 microM), a specific inhibitor of MAPK kinase (MEK) inhibited the p42/44 MAPK phosphorylation, indicating the specificity of the response. Furthermore, the MCP-1-induced phosphorylation of p42/44 MAPK was found to be blocked by pertussis toxin (100 ng/ml), tyrosine kinase inhibitor-genestein (10 ng/ml), PI3K inhibitor-wortmannin (20-200 microM), and anti-CCR2 antibody (2.5 microg/ml). Additionally, phosphorylation of JNK and activation of the transcription factor, c-Jun, were also noted in response to MCP-1 treatment. Lastly, the MCP1-induced p42/44 MAPK activity was correlated with the functional activation of macrophages by demonstrating the dose-specific inhibition of actin polymerization, macrophage-mediated tumor cell cytotoxicity, and tumor necrosis factor-alpha (TNF-alpha) transcription/production afforded by PD98059 in the MCP-1-treated macrophages. Taken together, these data suggest the involvement of the p42/44 MAPK/c-Jun pathway in the signal transduction process, leading to activation of murine peritoneal macrophages.
authors.affiliation: School of Biotechnology, Banaras Hindu University, Varanasi 221005, India. ajit.sodhi@lycos.com
authors.forename: Ajit
authors.initials: A
authors.lastname: Sodhi
authors.forename: Subhra K
authors.initials: SK
authors.lastname: Biswas
mesh_terms: D000199:Actins / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D019833:Genistein / Q000494:pharmacology; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000077191:Wortmannin
chemical_list: D000199:Actins; D000730:Androstadienes; D000911:Antibodies, Monoclonal; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016755:Proto-Oncogene Proteins c-jun; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D019833:Genistein; D037342:Pertussis Toxin; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000077191:Wortmannin