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
- Author(s)
- Schofield, L; Novakovic, S; Gerold, P; Schwarz, RT; McConville, MJ; Tachado, SD;
- Details
- Publication Year 1996-03-01,Volume 156,Issue #5,Page 1886-1896
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Publication Type
- Journal Article
- 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 adhesin expression and parasite cytoadherence. GPI-induced up-regulation of adhesin 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 malarial 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.
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Keywords
- NF-KAPPA-B; HUMAN CEREBRAL MALARIA; TUMOR-NECROSIS-FACTOR; FACTOR INDUCTION; SENSITIVE METHOD; TNF PRODUCTION; NITRIC-OXIDE; PROTEIN; FALCIPARUM; PHOSPHATIDYLINOSITOL
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Creation Date: 1996-03-01 12:00:00