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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 A¹

Munehisa Takahashi^2,*, Carole Galligan^2,*, Lino Tessarollo and Teizo Yoshimura^3,*

^* Laboratory of Molecular Immunoregulation, Cancer, and Inflammation Program, and Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702

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^/) 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^/ 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^/ 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^/ mice, thioglycolate- or zymosan-induced monocyte/macrophage accumulation was still reduced by 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

² M.T. and C.G. equally contributed to this work.

³ Address correspondence and reprint requests to Dr. Teizo Yoshimura, Building 559, Room 2, National Cancer Institute, Frederick, MD 21702. E-mail address: yoshimut{at}mail.nih.gov

⁴ Abbreviations used in this paper: KO, knockout; CAPE, caffeic acid phenethyl ester; ES, embryonic stem; PEC, peritoneal exudate cell; TG, thioglycolate; WT, wild type.