[Analysis of monocyte/macrophage function in a human MCAF/MCP-1 transgenic mouse].
MCAF/MCP-1 is a chemotactic cytokine which belongs to beta- or C-C chemokine subfamily. MCAF/MCP-1 activates not only monocytes but also other types of leukocytes. However, precise roles of MCAF/MCP-1 in vivo remain unclear. To elucidate these issues, we established a human MCAF/MCP-1 transgenic mouse (Tgm). The Tgm produced constitutively a high concentration of MCAF/MCP-1 (7-13 ng/ml) in the serum under the influence of beta-actin promoter in the vector of transgene. The expression of transgene was recognized in multiple organs, especially in lymphoid organs and an accumulation of macrophages was seen in these lymphoid organs. However, peritoneal macrophages of the Tgm exhibited reduced phagocytosis toward latex beads which had been injected intraperitoneally. It was also demonstrated that these Tgm had prolongation of liver granuloma reaction against the stimulation of zymosan. In contrast, activities of Fgr and Hck, macrophage-associated src-family protein tyrosine kinases, were increased in the peritoneal cells of Tgm. When peritoneal macrophages of Tgm were developed in a non-Tgm circumstance after bone marrow transplantation from Tgm into AKR, these macrophages exhibited increased expression of Mac-1. Moreover, when co-cultured with IFN-gamma, these macrophages produced a large amount of nitric oxide as compared to non-Tgm cells cultured in the same condition as Tgm cells. These findings suggested that the dysfunction of macrophages seen in human MCAF/MCP-1 Tgm in vivo was attributed to down-regulation and/or desensitization of receptors for MCAF/MCP-1 caused by the high concentration of MCAF/MCP-1.
Ato
M
M
Section of Pathology, Hokkaido University, Sapporo, Japan.
D000818:Animals; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry; D006099:Granuloma; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D010587:Phagocytosis / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000097:blood / Q000235:genetics / Q000502:physiology*; D019076:Transgenes
D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D009569:Nitric Oxide; D011505:Protein-Tyrosine Kinases