Iκb-ζ plays an important role in the ERK-dependent dysregulation of malaria parasite GPI-induced IL-12 expression

Jianzhong Zhu, Rebecca Weinberg, Xianzhu Wu, Nagaraj M. Gowda, Tatsushi Muta, Channe Gowda

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Plasmodium falciparum glycosylphosphatidylinositols (GPIs) have been proposed as malaria pathogenic factors based on their ability to induce proinflammatory responses in macrophages and malaria-like symptoms in mice. Parasite GPIs induce the production of inflammatory cytokines by activating the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways. Importantly, inhibition of the extracellular-signal-regulated kinase (ERK) pathway upregulates a subset of cytokines, including IL-12. We investigated the role of nuclear transcription factor, IκB-ζ, in the GPI-induced dysregulated expression of IL-12 on inhibition of the ERK pathway. GPIs efficiently induced the expression of IκB-ζ in macrophages regardless of whether cells were pretreated or untreated with ERK inhibitors, indicating that ERK has no role in IκB-ζ expression. However, on ERK inhibition followed by stimulation with GPIs, NF-κB binding to Il12b promoter κB site was markedly increased, suggesting that the ERK pathway regulates Il12b transcription. Knockdown of IκB-ζ using siRNA markedly reduced the GPI-induced IL-12 production and abrogated the dysregulated IL-12 production in ERK inhibited cells. Together these results demonstrate that ERK modulates IL-12 expression by regulating IκB-ζ-dependent binding of NF-κB transcription factors to Il12b gene promoter. Additionally, our finding that IκB-ζ can be knocked down efficiently in primary macrophages is valuable for studies aimed at gaining further insights into IκB-ζ function.

Original languageEnglish (US)
Pages (from-to)187-193
Number of pages7
JournalIUBMB Life
Volume64
Issue number2
DOIs
StatePublished - Jan 1 2012

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Glycosylphosphatidylinositols
Extracellular Signal-Regulated MAP Kinases
Interleukin-12
Malaria
Parasites
Macrophages
Transcription Factors
Cytokines
Proto-Oncogene Proteins c-akt
Transcription
Plasmodium falciparum
Mitogen-Activated Protein Kinases
Small Interfering RNA
Up-Regulation
Genes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Clinical Biochemistry
  • Cell Biology

Cite this

Zhu, Jianzhong ; Weinberg, Rebecca ; Wu, Xianzhu ; Gowda, Nagaraj M. ; Muta, Tatsushi ; Gowda, Channe. / Iκb-ζ plays an important role in the ERK-dependent dysregulation of malaria parasite GPI-induced IL-12 expression. In: IUBMB Life. 2012 ; Vol. 64, No. 2. pp. 187-193.
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abstract = "Plasmodium falciparum glycosylphosphatidylinositols (GPIs) have been proposed as malaria pathogenic factors based on their ability to induce proinflammatory responses in macrophages and malaria-like symptoms in mice. Parasite GPIs induce the production of inflammatory cytokines by activating the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways. Importantly, inhibition of the extracellular-signal-regulated kinase (ERK) pathway upregulates a subset of cytokines, including IL-12. We investigated the role of nuclear transcription factor, IκB-{\^I}¶, in the GPI-induced dysregulated expression of IL-12 on inhibition of the ERK pathway. GPIs efficiently induced the expression of IκB-{\^I}¶ in macrophages regardless of whether cells were pretreated or untreated with ERK inhibitors, indicating that ERK has no role in IκB-{\^I}¶ expression. However, on ERK inhibition followed by stimulation with GPIs, NF-κB binding to Il12b promoter κB site was markedly increased, suggesting that the ERK pathway regulates Il12b transcription. Knockdown of IκB-{\^I}¶ using siRNA markedly reduced the GPI-induced IL-12 production and abrogated the dysregulated IL-12 production in ERK inhibited cells. Together these results demonstrate that ERK modulates IL-12 expression by regulating IκB-{\^I}¶-dependent binding of NF-κB transcription factors to Il12b gene promoter. Additionally, our finding that IκB-{\^I}¶ can be knocked down efficiently in primary macrophages is valuable for studies aimed at gaining further insights into IκB-{\^I}¶ function.",
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Iκb-ζ plays an important role in the ERK-dependent dysregulation of malaria parasite GPI-induced IL-12 expression. / Zhu, Jianzhong; Weinberg, Rebecca; Wu, Xianzhu; Gowda, Nagaraj M.; Muta, Tatsushi; Gowda, Channe.

In: IUBMB Life, Vol. 64, No. 2, 01.01.2012, p. 187-193.

Research output: Contribution to journalArticle

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