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Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum: Cell signaling receptors, GPI structural requirement, and regulation of GPI activity.

Authors: Krishnegowda, G  Hajjar, AM  Zhu, J  Douglass, EJ  Uematsu, S  Akira, S  Woods, AS  Gowda, DC 
Citation: Krishnegowda G, etal., J Biol Chem 2004 Dec 28;.
Pubmed: (View Article at PubMed) PMID:15623512
DOI: Full-text: DOI:10.1074/jbc.M413541200

The glycosylphosphatidylinositol (GPI) anchors of Plasmodium falciparum are thought to be the major factors that contribute to malaria pathogenesis through their ability to induce proinflammatory responses. In this study, we identified the receptors for P. falciparum GPI-induced cell signaling that leads to proinflammatory responses, and studied the GPI structure-activity relationship. The data show that GPI-signaling is mediated mainly through recognition by TLR2 and to a lesser extent by TLR4. The activity of sn-2 lyso GPIs is comparable to that of the intact GPIs, whereas the activity of Man(3)-GPIs is about 80% that of the intact GPIs. The GPIs with three (intact GPIs and Man(3)-GPIs) and two fatty acids (sn-2 lyso GPIs) appear to differ considerably in the requirement of the auxiliary receptor, TLR1 or TLR6, for recognition by TLR2. The former are preferentially recognized by TLR2/TLR1, whereas the latter are favored by TLR2/TLR6. However, the signaling pathways initiated by all three GPI types are similar, involving the MyD88-dependent activation of ERK, JNK and p38, and NF-kappaB signaling pathways. The signaling molecules of these pathways differentially contribute to the production of various cytokines and nitric oxide (Zhu, J., et al. (2004) J. Biol. Chem., accompanying manuscript). Our data also show that GPIs are degraded by the macrophage surface phospholipases, predominantly into inactive species, indicating that the host can regulate GPI activity, at least in part, by this mechanism. These results imply that macrophage surface phospholipases play important roles in the GPI-induced innate immune response and malaria pathogenesis.

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CRRD Object Information
CRRD ID: 1304515
Created: 2005-01-05
Species: All species
Last Modified: 2005-01-05
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.