Delayed clearance of zymosan-induced granuloma and depressed phagocytosis of macrophages with concomitant up-regulated kinase activities of Src-family in a human monocyte chemoattractant protein-1 transgenic mouse

A human monocyte chemoattractant protein-1 (hMCP-1) transgenic mouse (Tgm) line which constitutively produces a large amount of hMCP-1 (7-13 ng/ml in the serum) was established. Although expression of the transgene was detect ed in various tissues, an accumulation of macrophages (M phi) was seen in o nly lymphoid organs which might be attributed to the high concentration of hMCP-1 in these organs. A reduced phagocytosis by peritoneal M phi in vivo and a delayed clearance of granulomas in the liver following zymosan admini stration were observed in these Tgm. However, peritoneal exudate cells (PEC ) from Tgm exhibited normal in vitro phagocytic activity and nitric oxide ( NO) production upon stimulation with IFN-gamma as compared with those from non-Tgm. In addition, high activities of src-family protein tyrosine kinase s (PTK), Fgr and Hck, were also noted in the peritoneal resident cells from Tgm, whereas the level of mitogen-activated protein kinase (MAPK) activity was almost the same as chat of non-Tgm. It was suggested that the low func tional activities of Tgm M phi seen in vivo were attributed to down-regulat ion of the unique transducing system of hMCP-1 signals under the influence of a high concentration of the hMCP-1. It seemed that the depressed functio ns were recovered when the peritoneal cells were released ex vivo from such a high hMCP-1 environment.