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

Jianzhong Zhu, Xianzhu Wu, Suchi Goel, Nagaraj M. Gowda, Sanjeev Kumar, Gowdahalli Krishnegowda, Gourav Mishra, Rebecca Weinberg, Guangfu Li, Matthias Gaestel, Tatsushi Muta, D. Channe Gowda

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30 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)15756-15761
Number of pages6
JournalJournal of Biological Chemistry
Volume284
Issue number23
DOIs
Publication statusPublished - 2009 Jun 5

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Zhu, J., Wu, X., Goel, S., Gowda, N. M., Kumar, S., Krishnegowda, G., Mishra, G., Weinberg, R., Li, G., Gaestel, M., Muta, T., & Gowda, D. C. (2009). MAPK-activated protein kinase 2 differentially regulates plasmodium falciparum glycosylphosphatidylinositol-inducedproduction of tumor necrosis Factor-α and interleukin-12 in macrophages. Journal of Biological Chemistry, 284(23), 15756-15761. https://doi.org/10.1074/jbc.M901111200