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Iκb‐ζ plays an important role in the ERK‐dependent dysregulation of malaria parasite GPI‐induced IL‐12 expression
Author(s) -
Zhu Jianzhong,
Weinberg Rebecca,
Wu Xianzhu,
Gowda Nagaraj M.,
Muta Tatsushi,
Gowda D. Channe
Publication year - 2012
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.592
Subject(s) - malaria , parasite hosting , mapk/erk pathway , biology , expression (computer science) , immunology , microbiology and biotechnology , signal transduction , computer science , world wide web , programming language
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. © 2011 IUBMB, IUBMB Life,, 2012