Abstract—Inflammatory response and chemotaxis of vascular wall cells play an important pathogenic role in the development of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant of monocytes. Besides the induction of monocyte recruitment, it has been suggested that MCP-1 may directly activate smooth muscle cells. We investigated whether MCP-1 affects the proliferation and cytokine production of human vascular smooth muscle cells (VSMCs) and determined the underlying signal transduction pathways. Stimulation of VSMCs with MCP-1 induced proliferation and resulted in a concentration- and time-dependent release of the proinflammatory cytokine interleukin-6 (IL-6). Pretreatment with pertussis toxin, GF109203X, and pyrrolidine dithiocarbamate inhibited MCP-1--dependent IL-6 release, suggesting the involvement of G_i proteins, protein kinase C, and nuclear factor-B (NF-B). MCP-1 also induced extracellular signal--regulated kinase, which, along with IL-6 release, was inhibited by pertussis toxin. PD98059 prevented MCP-1--induced extracellular signal--regulated kinase activation and cell proliferation. MCP-1 stimulated the binding activity of NF-B and of activator protein-1 (AP-1). As demonstrated by cis element double-stranded (decoy) oligonucleotides, NF-B was involved in IL-6 release by MCP-1, whereas proliferation was dependent on AP-1. The results clearly demonstrate that MCP-1 induces differential activation of NF-B and AP-1 in VSMCs. Thus, our data propose a new mechanism for the proatherogenic effect of MCP-1.