Glycosylphosphatidylinositol toxin of Plasmodium induces nitric oxide synthase expression in macrophages and vascular endothelial cells by a protein tyrosine kinase-dependent and protein kinase C-dependent signaling pathway
- Author(s)
- Tachado, SD; Gerold, P; McConville, MJ; Baldwin, T; Quilici, D; Schwarz, RT; Schofield, L;
- Details
- Publication Year 1996-03-01,Volume 156,Issue #5,Page 1897-1907
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Publication Type
- Journal Article
- Abstract
- In this study, we demonstrate that glycosylphosphatidylinositol (CPI) is a major toxin of Plasmodium falciparum origin responsible for nitric oxide (NO) production in host cells, Purified malarial GPI is sufficient to induce NO release in a time- and dose-dependent manner in macrophages and vascular endothelial cells, and regulates inducible NO synthase expression in macrophages, GPI-induced NO production was blocked by the NO synthase-specific inhibitor L-N-monomethylarginine. GPI also synergizes with IFN-gamma in regulating NO production, The structurally related molecules dipalmitoylphosphatidylinositol and iM4 glycoinositolphospholipid from Leishmania mexicana had no such activity, and the latter antagonized IFN-gamma-induced NO output, CPI activates macrophages by initiating an early onset tyrosine kinase-mediated signaling process, similar to that induced by total parasite extracts, The tyrosine kinase antagonists tyrphostin and genistein inhibited the release of NO by parasite extracts and by CPI, alone or in combination with IFN-gamma, demonstrating the involvement of one or more tyrosine kinases in the signaling cascade, GPI-induced NO release was also blocked by the protein kinase C inhibitor calphostin C, demonstrating a role for protein kinase C in GPI-mediated cell signaling, and by pyrrolidine dithiocarbamate, indicating the involvement of the NF-kappa B/c-rel family of transcription factors in cell activation, A neutralizing mAb to malarial GPI inhibited NO production induced by CPI and total malarial parasite extracts in human vascular endothelial cells and murine macrophages, indicating that CPI is a necessary agent of parasite origin in parasite-induced NO output, Thus, in contrast to dipalmitoylphosphatidylinositol and glycoinositolphospholipids of Leishmania, malarial CPI initiates a protein tyrosine kinase- and protein kinase C-mediated signal transduction pathway, regulating inducible NO synthase expression with the participation of NF-kappa B/c-rel, which leads to macrophage and vascular endothelial cell activation and downstream production of NO. These events may play a role in the etiology of severe malaria.
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Keywords
- NF-KAPPA-B; ADHESION MOLECULE-1 GENE; HUMAN CEREBRAL MALARIA; SENSITIVE METHOD; LEISHMANIA; LIPOPHOSPHOGLYCAN; INDUCTION; TRANSCRIPTION; TRANSDUCTION; PARASITES
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Creation Date: 1996-03-01 12:00:00