title: Iκb-ζ plays an important role in the ERK-dependent dysregulation of malaria parasite GPI-induced IL-12 expression.
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.
authors: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors: Jianzhong
authors: J
authors: Zhu
authors: Rebecca
authors: R
authors: Weinberg
authors: Xianzhu
authors: X
authors: Wu
authors: Nagaraj M
authors: NM
authors: Gowda
authors: Tatsushi
authors: T
authors: Muta
authors: D Channe
authors: DC
authors: Gowda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology* / Q000494:pharmacology; D002478:Cells, Cultured; D046508:Culture Techniques; D016207:Cytokines / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000276:immunology* / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D016778:Malaria, Falciparum / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010963:Plasmodium falciparum / Q000276:immunology*; D011401:Promoter Regions, Genetic; D034622:RNA Interference
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000953:Antigens, Protozoan; D016207:Cytokines; D058851:GPI-Linked Proteins; D053762:Interleukin-12 Subunit p40; D016328:NF-kappa B; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D048049:Extracellular Signal-Regulated MAP Kinases