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.
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.
Takahashi
Munehisa
M
Laboratory of Molecular Immunoregulation, Cancer, and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
Galligan
Carole
C
Tessarollo
Lino
L
Yoshimura
Teizo
T
D000818:Animals; D043422:Carboxypeptidases A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D002465:Cell Movement / Q000276:immunology*; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D013864:Thioglycolates / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000276:immunology; D015054:Zymosan / Q000008:administration & dosage / Q000494:pharmacology*
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D013864:Thioglycolates; D015054:Zymosan; D043422:Carboxypeptidases A; C503326:Cpa3 protein, mouse