title: Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity.
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 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 extracellular signal-regulated kinase, c-Jun N-terminal kinase, 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., 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033-0850, USA.
authors.forename: Gowdahalli
authors.initials: G
authors.lastname: Krishnegowda
authors.forename: Adeline M
authors.initials: AM
authors.lastname: Hajjar
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhu
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Douglass
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Amina S
authors.initials: AS
authors.lastname: Woods
authors.forename: D Channe
authors.initials: DC
authors.lastname: Gowda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D002241:Carbohydrates / Q000737:chemistry; D002460:Cell Line; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D017261:Glycosylphosphatidylinositols / Q000737:chemistry*; D006046:Gold / Q000737:chemistry; D006801:Humans; D007249:Inflammation; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology*; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D010740:Phospholipases / Q000378:metabolism; D010963:Plasmodium falciparum / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D002241:Carbohydrates; D017261:Glycosylphosphatidylinositols; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495368:TLR6 protein, human; C495369:Tlr6 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D006046:Gold; D048049:Extracellular Signal-Regulated MAP Kinases; D010740:Phospholipases