Chemokines are a large family of cytokines that control the trafficking of leukocytes.1 They participate in virtually all immune responses, from the sniffles to AIDS. There is great complexity to the action of chemokines, because of the large number of factors and because of the overlapping specificities for the seven known chemokine receptors. Identification of more of the cast of chemokines, where and under what circumstances they are produced, and on which cells they act, either alone or in concert, will lead to a better understanding of this complex system.
The alpha-chemokine family (C-X-C chemokines) in general acts on neutrophils and lymphocytes, while the beta-chemokines (C-C chemokines) tend to act on monocytes, lymphocytes, eosinophils and basophils. A subfamily of beta-chemokines includes monocyte chemoattractant proteins-1, -2, and -3 plus eotaxin. Now, MCP-4 has been added to this subfamily of human proteins2,3 and mouse MCP-5 to a list of related mouse proteins.4,5
MCP-4 was independently identified by two groups who cloned cDNA sequences with homology to beta-chemokines of the MCP subfamily. It is about 60% identical to the other MCPs and to eotaxin. It contains an N-terminal pyroglutamate, like the other MCPs but unlike eotaxin. MCP-4 is a potent chemoattractant for monocytes and eosinophils, and it induces histamine release from basophils. Like the other members of this subfamily, it shows no activity toward neutrophils. It acts on receptors CCR-2B (MCP-1 receptor) and CCR-3 (eotaxin receptor) but not on CCR-1 or CCR-5 (receptors for MIP-1 alpha, RANTES, and MCP-3).
The major constitutive expression of MCP-4 mRNA is in epithelial cells. There is no basal expression in endothelial cells, but expression could be induced by inflammatory cytokines, TNF-alpha and IL-1 alpha, with IFN-gamma potentiating these effects. Garcia-Zepada et al.3 hypothesize that MCP-4 functions as a hybrid of MCP-1, MCP-3, and eotaxin in recruiting leukocytes to epithelial surfaces.
Mouse MCP-5 was independently identified by two groups.4,5 It is not yet possible to definitively correlate mouse and human chemokines, so it is not clear whether this represents identification of a mouse homolog of a known human protein or of a new chemokine that will have a human homolog. In the case of mouse MCP-5 this question is made more difficult by differences observed in biological activity. Sarafi et al.5 found that mouse MCP-5 was a potent chemoattractant for monocytes but not for eosinophils, whereas Jia et al.4 found the opposite. Sarafi et al. also found that MCP-5 stimulated cells transfected with CCR-2 receptors but not those transfected with either CCR-1, CCR-3 (both on eosinophils), or CCR-5.