Cell type-specific activation of mitogen-activated protein kinases by CpG-DNA controls interleukin-12 release from antigen-presenting cells

Activation of antigen-presenting cells (APCs) by invariant constituents of pathogens such as lipopolysaccharide (LPS) or bacterial DNA (CpG-DNA) initi ates immune responses. We have analyzed the mitogen-activated protein kinas e (MAPK) pathways triggered by CpG-DNA and their significance for cytokine production in two subsets of APCs, i.e. macrophages and dendritic cells (DC s). We found that CpG-DNA induced extracellular signal-regulated kinase (ER K) activity in macrophages in a classic MEK-dependent way. This pathway up- regulated tumor necrosis factor production but down-regulated interleukin ( IL)-12 production. However, in DCs, which produce large amounts of IL-12, C pG-DNA and LPS failed to induce ERK activity. Consistent with a specific ne gative regulatory role for ERK in macrophages, chemical activation of this pathway in DCs suppressed CpG-DNA-induced IL-12 production. Overall, these results imply that differential activation of MAP kinase pathways is a basi c mechanism by which distinct subsets of innate immune cells regulate their effector functions.