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

Gowdahalli Krishnegowda, Adeline M. Hajjar, Jianzhong Zhu, Erika J. Douglass, Satoshi Uematsu, Shizuo Akira, Amina S. Woods, D. Chaime Gowda

Research output: Contribution to journalArticle

Abstract

The glycosylphosphatidylinositol (GPI) anchors of Plasmodium falciparum have been proposed 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 with that of the intact GPIs, whereas the activity of Man3-GPIs is about 80% that of the intact GPIs. The GPIs with three (intact GPIs and Man3-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 extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 and NF-κB-signaling pathways. The signaling molecules of these pathways differentially contribute to the production of various cytokines and nitric oxide (Zhu, J., Krishnegowda, G., and Gowda, D. C. (2004) J. Biol. Chem. 280, 8617-8627). 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 responses and malaria pathogenesis.

Original languageEnglish (US)
Pages (from-to)8606-8616
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number9
DOIs
StatePublished - Mar 4 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry

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