+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



Journal of Immunology 156(5): 1897-1907



In this study, we demonstrate that glycosylphosphatidylinositol (GPI) 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. GPI 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 GPI, 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 GPI and total malarial parasite extracts in human vascular endothelial cells and murine macrophages, indicating that GPI is a necessary agent of parasite origin in parasite-induced NO output. Thus, in contrast to dipalmitoylphosphatidylinositol and glycoinositolphospholipids of Leishmania, malarial GPI 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.

Please choose payment method:






(PDF emailed within 1 workday: $29.90)

Accession: 002853559

Download citation: RISBibTeXText

PMID: 8596042


Related references

ADP signaling in vascular endothelial cells: ADP-dependent activation of the endothelial isoform of nitric-oxide synthase requires the expression but not the kinase activity of AMP-activated protein kinase. Journal of Biological Chemistry 284(47): 32209-32224, 2009

A constituent of green tea, epigallocatechin-3-gallate, activates endothelial nitric oxide synthase by a phosphatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and Akt-dependent pathway and leads to endothelial-dependent vasorelaxation. Journal of Biological Chemistry 279(7): 6190-6195, 2004

Endothelin-1 impairs nitric oxide signaling in endothelial cells through a protein kinase Cdelta-dependent activation of STAT3 and decreased endothelial nitric oxide synthase expression. Dna and Cell Biology 28(11): 543-553, 2009

Regulation of the endothelial nitric oxide synthase gene by a protein tyrosine kinase-dependent pathway. Nephrology Dialysis Transplantation 12(9): A12, 1997

Hepatocyte Growth Factor Stimulates Nitric Oxide Production through Endothelial Nitric Oxide Synthase Activation by the Phosphoinositide 3-Kinase/Akt Pathway and Possibly by Mitogen-Activated Protein Kinase Kinase in Vascular Endothelial Cells. Hypertension Research 27(11): 887-895, 2004

Hepatocyte growth factor stimulates nitric oxide production through endothelial nitric oxide synthase activation by the phosphoinositide 3-kinase/Akt pathway and possibly by mitogen-activated protein kinase kinase in vascular endothelial cells. Hypertension Research 27(11): 887-895, 2004

Early signaling events by endotoxin in PC12 cells: Involvement of tyrosine kinase, constitutive nitric oxide synthase, cGMP-dependent protein kinase, and Ca-2+ channels. Journal of Neuroscience Research 45(3): 216-225, 1996

Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. Journal of Biological Chemistry 274(46): 33057-33063, 1999

Activation of the mitogen activated protein kinase extracellular signal-regulated kinase 1 and 2 by the nitric oxide-cGMP-cGMP-dependent protein kinase axis regulates the expression of matrix metalloproteinase 13 in vascular endothelial cells. Molecular Pharmacology 62(4): 927-935, 2002

Protein kinase Cα phosphorylates a novel argininosuccinate synthase site at serine 328 during calcium-dependent stimulation of endothelial nitric-oxide synthase in vascular endothelial cells. Journal of Biological Chemistry 287(31): 26168-26176, 2012

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. Journal of Immunology 156(5): 1886-1896, 1996

Ca superscript 2+(B- and Protein Kinase C-dependent Signaling Pathway for Nuclear Factor-(Sm(BB Activation, Inducible Nitric-oxide Synthase Expression, and Tumor Necrosis Factor-(Sa(B Production in Lipopolysaccharide-stimulated Rat Peritoneal Macrophages. Journal of biological chemistry20 281(42): 31337-31347, 2006

Intracellular signaling of tumor necrosis factor-alpha in brain microvascular endothelial cells is mediated by a protein tyrosine kinase and protein kinase C-dependent pathway. Journal of Neuroimmunology 70(2): 199-206, 1996

Effects of protein kinase C and motigen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway on mRNA level of inducible nitric oxide synthase in Tca8113 cells. Hua Xi Kou Qiang Yi Xue Za Zhi 36(2): 133-139, 2018

Ca2+- and protein kinase C-dependent signaling pathway for nuclear factor-kappaB activation, inducible nitric-oxide synthase expression, and tumor necrosis factor-alpha production in lipopolysaccharide-stimulated rat peritoneal macrophages. Journal of Biological Chemistry 281(42): 31337-31347, 2006