Clinical manifestations of tuberculosis are closely associated with the initial responses of macrophages to mycobacteria. In this study, we investigated the signal transduction pathways for the secretion of cytokines and chemokines [tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, IL-8, and monocyte chemotactic protein-1 (MCP-1)] in human blood monocytes infected with Mycobacterium tuberculosis H37Rv. M. tuberculosis H37Rv infection induced the secretion of significant amounts of TNF-alpha, IL-10, IL-8, and MCP-1 from human blood monocytes. Analysis of mitogen-activated protein kinase (MAPK) activation [extracellular signal-regulated kinase 1/2 (ERK) and p38 kinase] showed rapid phosphorylation of both subfamilies in response to M. tuberculosis H37Rv. Using highly specific inhibitors of p38 (SB203580) and of MEK-1 (U0126 and PD98059), we found that both p38 and ERK were essential for M. tuberculosis H37Rv-induced TNF-alpha production, whereas activation of the p38 pathway, but not that of ERK, was essential for M. tuberculosis H37Rv-induced IL-10 production. Interestingly, the ERK pathway, but not that of p38, was critical for MCP-1 secretion from human blood monocytes infected with M. tuberculosis H37Rv. However, IL-8 secretion was regulated neither by ERK1/2 nor p38 MAPK. Collectively, these results suggest that induction of the MAPK pathway is required for the expression of TNF-alpha. IL-10, and MCP-1 by human blood monocytes during M. tuberculosis H37Rv infection.