Functional roles of extracellular signal-related kinase (ERK) activation in dendritic-cell (DC) maturation have been unclear. In the present study, we investigated the ERK pathway in tumor necrosis factor (TNF)-alpha-induced maturation of murine spleen-derived DC. TNF-alpha increased surface expressions of major histocompatibility (MHC) and costimulatory molecules on DC in a dose-dependent manner. High (40 ng/ml) and low (0.4 ng/ml) concentrations of TNF-alpha markedly enhanced ERK1/2 activation in DC, and this activation was blocked completely by PD98059, a selective inhibitor of the ERK pathway. When DC were treated with TNF-alpha at a low but not a high concentration, PD98059 notably enhanced surface expressions of the MHC and costimulatory molecules and allostimulatory capability of the DC. Interleukin (IL)-12 production was enhanced significantly by PD98059 in DC treated with low or high concentration of TNF-alpha. These findings suggest that TNF-alpha-induced ERK activation negatively controls maturation and IL-12 production in murine DC.