MAPK-activated Protein Kinase 2 Differentially Regulates Plasmodium falciparum Glycosylphosphatidylinositol-induced Production of Tumor Necrosis Factor-α and Interleukin-12 in Macrophages

Abstract

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-␣ (TNF-␣) 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-␣ and IL-12. Although TNF-␣ 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-␣ 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-B 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-␣ 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.

Mycobacterium tuberculosislipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b

“…In particular, mice that lack MK2 show increased stress resistance and survive an LPSinduced endotoxic shock/cytokine storm due to decreased TNF production with no change in TNF receptor-mediated signaling (34). MK2 deficiency in mice results in increased susceptibility to Listeria monocytogenes infection (35), and MK2 differentially regulates Plasmodium falciparum glycosylphosphatidylinositolinduced production of TNF in mouse macrophages (36). These findings indicate an important role for MK2 in host defense against intracellular pathogens through the regulation of TNF production required for activation of antimicrobial effecter mechanisms.…”

Roles of the ERK MAPK in the regulation of proinflammatory and apoptotic responses in chicken macrophages infected with H9N2 avian influenza virus

“…ERK is evidently involved in the regulation of inflammatory responses in a few studies on other microorganisms as well. Two of the major proinflammatory cytokines, TNF-a and IL-12, produced in Plasmodium falciparum glycosylphosphatidylinositol-stimulated macrophages, can be effectively regulated by the ERK inhibitor U0126 (Zhu et al, 2009). The MAPK-activated protein kinase 2 (MK2), which is targeted by both ERK and p38, has also shown a regulatory effect on the expression of TNF-a and IL-12, and MK2 can be inhibited by U0126 (Zhu et al, 2009).…”

“…Two of the major proinflammatory cytokines, TNF-a and IL-12, produced in Plasmodium falciparum glycosylphosphatidylinositol-stimulated macrophages, can be effectively regulated by the ERK inhibitor U0126 (Zhu et al, 2009). The MAPK-activated protein kinase 2 (MK2), which is targeted by both ERK and p38, has also shown a regulatory effect on the expression of TNF-a and IL-12, and MK2 can be inhibited by U0126 (Zhu et al, 2009). Similarly, the inhibition of ERK as well as p38 pathways significantly decreased the IL-1b response induced by Vibrio cholerae and its flagellin in human Upregulation of FasL and TNF-a transcripts in U0126-treated HTC cells.…”

The role of Vitamin D in malaria

“…Malaria parasite development in the mosquito is regulated by a conserved MAPK signaling pathway that mediates the effects of an ingested cytokine [132]. ERK and p38 pathway regulate TNF-α and IL-12 production in macrophage-stimulated with purified P. falciparum GPI [133]. Human p38 mitogen-activated protein kinase inhibitor drugs, such as pyridinylimidazole RWJ67657 and the pyrrolobenzimidazole RWJ68198, inhibit P. falciparum replication [134].…”