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, Krishne Gowda, Gourav Mishra, Rebecca Weinberg, Guangfu Li, Matthias Gaestel, Tatsushi Muta, Channe Gowda

Research output: Contribution to journalArticle

29 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 (US)
Pages (from-to)15756-15761
Number of pages6
JournalJournal of Biological Chemistry
Volume284
Issue number23
DOIs
StatePublished - Jun 5 2009

Fingerprint

Glycosylphosphatidylinositols
Macrophages
Plasmodium falciparum
Interleukin-12
Protein Kinases
Tumor Necrosis Factor-alpha
Malaria
Genes
Messenger RNA
Phosphorylation
MAP Kinase Signaling System
Toll-Like Receptors
RNA Stability
Protein Biosynthesis
Protein Kinase Inhibitors
Communicable Diseases
Cytokines
Ligands

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Zhu, Jianzhong ; Wu, Xianzhu ; Goel, Suchi ; Gowda, Nagaraj M. ; Kumar, Sanjeev ; Gowda, Krishne ; Mishra, Gourav ; Weinberg, Rebecca ; Li, Guangfu ; Gaestel, Matthias ; Muta, Tatsushi ; Gowda, Channe. / MAPK-activated protein kinase 2 differentially regulates plasmodium falciparum glycosylphosphatidylinositol-inducedproduction of tumor necrosis Factor-α and interleukin-12 in macrophages. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 23. pp. 15756-15761.
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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.",
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MAPK-activated protein kinase 2 differentially regulates plasmodium falciparum glycosylphosphatidylinositol-inducedproduction of tumor necrosis Factor-α and interleukin-12 in macrophages. / Zhu, Jianzhong; Wu, Xianzhu; Goel, Suchi; Gowda, Nagaraj M.; Kumar, Sanjeev; Gowda, Krishne; Mishra, Gourav; Weinberg, Rebecca; Li, Guangfu; Gaestel, Matthias; Muta, Tatsushi; Gowda, Channe.

In: Journal of Biological Chemistry, Vol. 284, No. 23, 05.06.2009, p. 15756-15761.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MAPK-activated protein kinase 2 differentially regulates plasmodium falciparum glycosylphosphatidylinositol-inducedproduction of tumor necrosis Factor-α and interleukin-12 in macrophages

AU - Zhu, Jianzhong

AU - Wu, Xianzhu

AU - Goel, Suchi

AU - Gowda, Nagaraj M.

AU - Kumar, Sanjeev

AU - Gowda, Krishne

AU - Mishra, Gourav

AU - Weinberg, Rebecca

AU - Li, Guangfu

AU - Gaestel, Matthias

AU - Muta, Tatsushi

AU - Gowda, Channe

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N2 - 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.

AB - 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.

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