MAPK-activated protein kinase 2 differentially regulates plasmodium falciparum glycosylphosphatidylinositol-inducedproduction of tumor necrosis Factor-α and interleukin-12 in macrophages

Proinflammatory responses induced by Plasmodium falciparum glycosylphosphatidylinositols (GPIs) are thought to be involved in malaria pathogenesis. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2) in the regulation of tumor necrosis factor-α (TNF-α) and interleukin (IL)-12, two of the major inflammatory cytokines produced by macrophages stimulated with GPIs. We show that MK2 differentially regulates the GPI-induced production of TNF-α and IL-12. Although TNF-α production was markedly decreased, IL-12 expression was increased by 2-3-fold in GPI-stimulated MK2^-/- macrophages compared with wild type (WT) cells. MK2^-/-macrophages produced markedly decreased levels of TNF-α than WT macrophages mainly because of lower mRNA stability and translation. In the case of IL-12, mRNA was substantially higher in MK2^-/-macrophages than WT. This enhanced production is due to increased NF-κB binding to the gene promoter, a markedly lower level expression of the transcriptional repressor factor c-Maf, and a decreased binding of GAP-12 to the gene promoter in MK2^-/-macrophages. Thus, our data demonstrate for the first time the role of MK2 in the transcriptional regulation of IL-12. Using the protein kinase inhibitors SB203580 and U0126, we also show that the ERK and p38 pathways regulate TNF-α and IL-12 production, and that both inhibitors can reduce phosphorylation of MK2 in response to GPIs and other toll-like receptor ligands. These results may have important implications for developing therapeutics for malaria and other infectious diseases.