Monocyte Chemoattractant Protein-1-Induced Activation of p42/44 MAPK and c-Jun in Murine Peritoneal Macrophages: A Potential Pathway for Macrophage Activation
- 1 May 2002
- journal article
- research article
- Published by Mary Ann Liebert Inc in Journal of Interferon & Cytokine Research
- Vol. 22 (5), 517-526
- https://doi.org/10.1089/10799900252981990
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 μM), 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 μM), and anti-CCR2 antibody (2.5 μg/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-α (TNF-α) 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.Keywords
This publication has 44 references indexed in Scilit:
- Expression and activation of RAS and mitogen‐activated protein kinases in macrophages treatedin vitrowith cisplatin: Regulation by kinases, phosphatases and Ca2+/calmodulinImmunology & Cell Biology, 1999
- DiscussionCytokine & Growth Factor Reviews, 1998
- Differential Regulation of G-protein-mediated Signaling by Chemokine ReceptorsJournal of Biological Chemistry, 1996
- Interleukin-8 Regulation of the Ras/Raf/Mitogen-activated Protein Kinase Pathway in Human NeutrophilsJournal of Biological Chemistry, 1996
- PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-activated Protein Kinase Kinase in Vitro and in VivoJournal of Biological Chemistry, 1995
- JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domainCell, 1994
- The origin and function of tumor-associated macrophagesImmunology Today, 1992
- Phosphorylation of c-jun mediated by MAP kinasesNature, 1991
- Macrophage infiltration and growth of sarcoma clones expressing different amounts of monocyte chemotactic protein/JEInternational Journal of Cancer, 1991
- Recognition and destruction of neoplastic cells by activated macrophages: discrimination of altered selfBiochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1988