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.
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Authors | L Schofield, S Novakovic, P Gerold, R T Schwarz, M J McConville, S D Tachado |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 156
Issue 5
Pg. 1886-96
(Mar 01 1996)
ISSN: 0022-1767 [Print] United States |
PMID | 8596041
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cell Adhesion Molecules
- E-Selectin
- Glycosylphosphatidylinositols
- Protozoan Proteins
- Vascular Cell Adhesion Molecule-1
- Intercellular Adhesion Molecule-1
- Protein-Tyrosine Kinases
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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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