Monocyte chemoattractant protein-1 (MCP-1) and angiotensin II (Ang II) in adipose tissue are thought to induce systemic insulin resistance in rodents; but the precise mechanism is not fully clarified. We examined the mechanism of Ang II-induced and/or tumor necrosis factor-alpha (TNF-alpha)-induced MCP-1 production from 3T3-L1 preadipocytes. The MCP-1 protein and MCP-1 mRNA expression in 3T3-L1 preadipocytes were increased significantly by stimulation with TNF-alpha. We found no significant increase in MCP-1 concentrations by Ang II alone; but it enhanced the TNF-alpha-induced MCP-1 mRNA expression in a dose-dependent manner. Then, we examined the effect of Ang II and/or TNF-alpha on phosphorylation of extracellular signal-regulated kinase (ERK), p38MAPK, and IkappaB-alpha. Ang II and TNF-alpha clearly enhanced ERK and p38MAPK phosphorylation. IkappaB-alpha phosphorylation was enhanced by TNF-alpha, but not by Ang II. The MCP-1 mRNA expression induced by TNF-alpha and co-stimulation with Ang II was inhibited by either ERK inhibitor, p38MAPK inhibitor or NF-kappaB inhibitor. Moreover, Ang II enhanced the activation of AP-1 (c-fos) induced by TNF-alpha. Our results suggest that Ang II may serve as an additional stimulus on the TNF-alpha-induced MCP-1 production through the ERK-and p38MAPK-dependent pathways probably due to AP-1 activation.