Low-Dose Lipopolysaccharide Modifies the Production of IL-12 by Dendritic Cells in Response to Various Cytokines

Dendritic cell (DC) activation is triggered by cytokines, including tumor necrosis factor (TNF)-alpha, and microbe components, including lipopolysaccharide (LPS). During the initial stage of infection, the microbe components appear to be present at low concentration. To determine the role of low-dose microbe-components in DC activation during the initial stage of infection, we examined the effects of low-dose LPS on cytokine-induced maturation and function of DCs. Low-dose LPS (1 ng/ml) treatment of DCs had only additive effects on the expression of CD86 and major histocompatibility complex class II induced by various cytokines, including interleukin (IL)-1 beta, TNF-alpha and interferon (IFN)-gamma. IL-1 beta alone significantly induced IL-12 production in DCs, whereas TNF-alpha or IFN-gamma induced modest levels of IL-12 production. When low-dose LPS (1 ng/ml), which only slightly induced IL-12 production, was added to the culture, only an additive effect was seen on IL-1 beta-induced IL-12 production. In contrast, low-dose LPS synergistically enhanced TNF-alpha-or IFN-gamma-induced IL-12 production. SB203580, a specific inhibitor of p38 MAPK, markedly inhibited TNF-alpha-or IFN-gamma-induced IL-12-production either in the absence or presence of LPS, but showed only modest effects on IL-1 beta-induced IL-12-production. These findings suggest that the p38 MAPK pathway is essential for the synergistic IL-12 production induced by TNF-alpha-or IFN-gamma in combination with low-dose LPS in DC.