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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.
AuthorsL Schofield, S Novakovic, P Gerold, R T Schwarz, M J McConville, S D Tachado
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 156 Issue 5 Pg. 1886-96 (Mar 01 1996) ISSN: 0022-1767 [Print] United States
PMID8596041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cell Adhesion Molecules
  • E-Selectin
  • Glycosylphosphatidylinositols
  • Protozoan Proteins
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Protein-Tyrosine Kinases
Topics
  • Animals
  • Cell Adhesion (immunology)
  • Cell Adhesion Molecules (biosynthesis, drug effects)
  • E-Selectin (biosynthesis, drug effects)
  • Endothelium, Vascular (enzymology, immunology, metabolism)
  • Glycosylphosphatidylinositols (immunology, isolation & purification, toxicity)
  • Host-Parasite Interactions
  • Humans
  • Intercellular Adhesion Molecule-1 (biosynthesis, drug effects)
  • Leukocytes, Mononuclear (drug effects, enzymology, immunology)
  • Phosphorylation
  • Plasmodium falciparum (chemistry, immunology, physiology)
  • Protein-Tyrosine Kinases (metabolism)
  • Protozoan Proteins (immunology, isolation & purification, toxicity)
  • Signal Transduction (immunology)
  • Up-Regulation (immunology)
  • Vascular Cell Adhesion Molecule-1 (biosynthesis, drug effects)

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