Monocyte Chemoattractant Protein-1 (MCP-1), Not MCP-3, Is the Primary Chemokine Required for Monocyte Recruitment in Mouse Peritonitis Induced with Thioglycollate or Zymosan A

• Published in: The Journal of immunology (1950) 2009-09, Vol.183 (5), p.3463-3471
• Main Authors: Takahashi, Munehisa, Galligan, Carole, Tessarollo, Lino, Yoshimura, Teizo
• Format: Article
• Language: English
• Subjects: Animals; Carboxypeptidases A - antagonists & inhibitors; Carboxypeptidases A - biosynthesis; Carboxypeptidases A - physiology; Cell Movement - immunology; Chemokine CCL2 - deficiency; Chemokine CCL2 - genetics; Chemokine CCL2 - physiology; Disease Models, Animal; Down-Regulation - genetics; Down-Regulation - immunology; Gene Deletion; Lipopolysaccharides - pharmacology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes - cytology; Monocytes - immunology; Monocytes - metabolism; Peritonitis - chemically induced; Peritonitis - immunology; Peritonitis - pathology; Thioglycolates - administration & dosage; Thioglycolates - pharmacology; Up-Regulation - immunology; Zymosan - administration & dosage; Zymosan - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0802812

MCP-1/CCL2 plays a critical role in monocyte recruitment into sites of immune responses and cancer. However, the role of other MCPs remains unclear. In this study, we generated a novel MCP-1-deficient (designated as MCP-1(Delta/Delta)) mouse model by deleting a 2.3-kb DNA fragment from the mouse genome using the Cre/loxP system. MCP-1 was not produced by LPS-activated MCP-1(Delta/Delta) macrophages; however, the production of MCP-3, coded by the immediate downstream gene, was significantly increased. In contrast, macrophages from another mouse line with a neo-gene cassette in intron 2 produced a significantly lower level of MCP-1 and MCP-3. Decreased MCP-3 production was also detected in previously generated MCP-1-deficient mice in which a neo-gene cassette was inserted in exon 2 (designated as MCP-1 knockout (KO)). Altered MCP-1 and/or MCP-3 production was also observed in vivo in each mouse model in response to i.p. injection of thioglycolate or zymosan. The up- and down-regulation of MCP-3 production in MCP-1(Delta/Delta) and MCP-1 KO mice, respectively, provided us with a unique opportunity to evaluate the role for MCP-3. Despite the increased MCP-3 production in MCP-1(Delta/Delta) mice, thioglycolate- or zymosan-induced monocyte/macrophage accumulation was still reduced by approximately 50% compared with wild-type mice, similar to the reduction detected in MCP-1 KO mice. Thus, up-regulated MCP-3 production did not compensate for the loss of MCP-1, and MCP-3 appears to be a less effective mediator of monocyte recruitment than MCP-1. Our results also indicate the presence of other mediators regulating the recruitment of monocytes in these models.