Monocyte chemoattractant protein-1 (MCP-1), a chemotactic cytokine, acts in vitro as a chemotactic and activating factor for multiple types of leukocytes. To determine the chemotactic and activating effects of MCP-1 in vivo, we constructed transgenic mice that express human MCP-1 in type II alveolar epithelial cells and secrete it into the bronchoalveolar space. We found that MCP-1 overexpression led to a marked increase in the numbers of both monocytes and lymphocytes that could be recovered by bronchoalveolar lavage. This accumulation of mononuclear leukocytes could be reversed by the administration of an MCP-1-blocking Ab. In spite of its chemotactic effect, MCP-1 expression did not cause the inflammatory activation of accumulated leukocytes. Lungs of MCP-1 transgenic mice also showed no morphologic evidence of inflammation. However, MCP-1 mice had an increased sensitivity to other inflammatory stimuli. MCP-1 mice treated with either i.p. LPS or i.v. yeast wall glucan developed consolidated pulmonary infiltrates consisting predominantly of macrophages. Nontransgenic mice developed no such infiltrates. These results demonstrate that MCP-1 is chemotactic for monocytes and lymphocytes in vivo and that MCP-1 expression alone does not cause inflammatory activation of cells, but leads to an enhanced inflammatory response upon treatment with other stimuli.