title: Glycosylphosphatidylinositol toxin of Plasmodium up-regulates intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expression in vascular endothelial cells and increases leukocyte and parasite cytoadherence via tyrosine kinase-dependent signal transduction.
abstract: In this study we demonstrate that glycosylphosphatidylinositol (GPI) of malaria parasite origin directly increases cell adhesion molecule expression in purified HUVECs in a dose- and time-dependent manner, resulting in a marked increase in parasite and leukocyte cytoadherence to these target cells. The structurally related glycolipids dipalmitoyl-phosphatidylinositol and iM4 glycoinositolphospholipid of Leishmania mexicana had no such activity. Malarial GPI exerts this effect by activation of an endogenous GPI-based signal transduction pathway in endothelial cells. GPI induces rapid onset tyrosine phosphorylation of multiple intracellular substrates within 1 min of addition to cells in a dose-dependent manner. This activity can be blocked by the protein tyrosine kinase-specific antagonist herbimycin A, genistein, and tyrphostin. These tyrosine kinase antagonists also inhibit GPI-mediated up-regulation of adhesion expression and parasite cytoadherence. GPI-induced up-regulation of adhesion expression and parasite cytoadherence can also be blocked by the NF kappa B/c-rel antagonist pyrrolidine-dithiocarbamate, suggesting the involvement of this family of transcription factors in GPI-induced adhesin expression. The direct activation of endothelial cells by GPI does not require the participation of TNF or IL-1. However, GPI is also responsible for the indirect pathway of increased adhesin expression mediated by TNF and IL-1 output from monocytes/macrophages. Total parasite extracts also up-regulate adhesin expression and parasite cytoadherence in HUVECs, and this activity is blocked by a neutralizing mAb to malaria GPI, suggesting that GPI is the dominant agent of parasite origin responsible for this activity. Thus, a parasite-derived GPI toxin activates vascular endothelial cells by tyrosine kinase-mediated signal transduction, leading to NF kappa B/c-rel activation and downstream expression of adhesins, events that may play a central role in the etiology of cerebral malaria.
authors.affiliation: Immunoparasitology Unit, Royal Melbourne Hospital, Victoria, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Schofield
authors.forename: S
authors.initials: S
authors.lastname: Novakovic
authors.forename: P
authors.initials: P
authors.lastname: Gerold
authors.forename: R T
authors.initials: RT
authors.lastname: Schwarz
authors.forename: M J
authors.initials: MJ
authors.lastname: McConville
authors.forename: S D
authors.initials: SD
authors.lastname: Tachado
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000187:drug effects; D019040:E-Selectin / Q000096:biosynthesis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D017261:Glycosylphosphatidylinositols / Q000276:immunology / Q000302:isolation & purification / Q000633:toxicity*; D006790:Host-Parasite Interactions; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000737:chemistry / Q000276:immunology* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015800:Protozoan Proteins / Q000276:immunology / Q000302:isolation & purification / Q000633:toxicity; D015398:Signal Transduction / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D015815:Cell Adhesion Molecules; D019040:E-Selectin; D017261:Glycosylphosphatidylinositols; D015800:Protozoan Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D011505:Protein-Tyrosine Kinases