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

Abstract

SummaryPlasmodium 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 mitogenactivated protein kinase (MAPK) and NF-jB 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, IjB-f, in the GPI-induced dysregulated expression of IL-12 on inhibition of the ERK pathway. GPIs efficiently induced the expression of IjB-f in macrophages regardless of whether cells were pretreated or untreated with ERK inhibitors, indicating that ERK has no role in IjB-f expression. However, on ERK inhibition followed by stimulation with GPIs, NF-jB binding to Il12b promoter jB site was markedly increased, suggesting that the ERK pathway regulates Il12b transcription. Knockdown of IjB-f 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 IjB-f-dependent binding of NF-jB transcription factors to Il12b gene promoter. Additionally, our finding that IjB-f can be knocked down efficiently in primary macrophages is valuable for studies aimed at gaining further insights into IjB-f function.

The Glycosylphosphatidylinositol Transamidase Complex Subunit PbGPI16 of Plasmodium berghei Is Important for Inducing Experimental Cerebral Malaria

“…PbGPI16 deficiency reduces ECM development in C57BL/6 mice. Given that GPIs are important causes of ECM (11)(12)(13)(14), we wanted to investigate whether decreased GPIs in the ⌬pbgpi16 mutant could alter the ability of the parasites to induce ECM. Groups of 10 mice were infected with either WT P. berghei ANKA or the ⌬pbgpi16 line by intravenous injection of 10 6 pRBCs.…”

“…pathway mediated by Toll-like receptors (TLRs). This activation triggers the downstream proinflammatory responses (13,15,16).…”

Atypical IκB proteins in immune cell differentiation and function

“…Furthermore, the LPS-induced mRNA expression of GM-CSF and G-CSF in peritoneal macrophages strongly depends on IκBζ [34]. Extracellular-signal-regulated kinase (ERK) inhibition in macrophages, did not affect the expression of IκBζ, indicating that the ERK-pathway is dispensable for IκBζ expression [69]. Furthermore, it was suggested that IκBζ is an essential regulator for the tri-methylation of H3K4 (Histone 3 Lysine 4), which is an epigenetic marker of transcriptionally active chromatin [67].…”

Interferons and Interferon Regulatory Factors in Malaria

“…For the liver stage of the infection, Plasmodium RNA is the only malarial ligand discovered so far [92]. In the blood stage, several ligands have been identified, such as GPI [62, 99–103], Hz [63, 104, 145], CpG DNA bound on Hz [105], host fibrinogen [106], heme [107, 108], microparticles [109], AT-rich motifs in malarial genome [61], Plasmodium DNA/RNA [85], P. falciparum tyrosyl-tRNA synthetase ( Pf TyrRS) [111], and P. falciparum high mobility group box protein (P f HMGB) [112]. All the different malarial ligands and their respective signaling molecules involved to induce an immune response are listed in Table 2.…”

“…Following that, nuclear translocations of transcription factor such as NF- κ B and AP-1, comprising the activation of transcription factor-2/c-Jun (ATF-2/c-Jun) [100, 102], stimulate production of proinflammatory cytokines such as TNF- α , IL-6, IL-12, and nitric oxide (NO) [100, 102, 154]. Interaction of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, zeta (I κ B- ζ ) with NF-kB, promotes IL-12 production [103]. However, the concentration of GPI on the surface of merozoites is too low to account for this potent stimulatory effect observed [155].…”