Plasmodium falciparum Glycosylphosphatidylinositol-induced TNF-α Secretion by Macrophages is Mediated without Membrane Insertion or Endocytosis

Matam Vijaykumar, Ramachandra S. Naik, Channe Gowda

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

The glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum are believed to contribute to the pathogenesis of malaria by inducing the secretion of proinflammatory cytokines by macrophages. Previous studies have shown that P. falciparum GPIs elicit toxic immune responses by protein tyrosine kinase (PTK)- and protein kinase C (PKC)-mediated cell signaling pathways, which are activated by the carbohydrate and acyl moieties of the intact GPIs, respectively. In this study, we show that induction of TNF-α by P. falciparum GPIs in macrophages is mediated by the recognition of the distal fourth mannose residue. This event is critical but not sufficient for the productive cell signaling; interaction by the acylglycerol moiety of GPIs is also required. These novel interactions are coupled to previously demonstrated PTK and PKC pathways, since the specific inhibitors of these kinases effectively blocked the GPI-induced TNF-α production. Surprisingly, sn-2 lyso-GPIs were also able to elicit TNF-α secretion. Contrary to the prevailing notion, GPIs are neither inserted to the plasma membranes nor endocytosized. Thus, this study defines the GPI structural requirements and reveals a novel mechanism for the outside-in activation of cell signaling by P. falciparum GPIs in inducing proinflammatory responses.

Original languageEnglish (US)
Pages (from-to)6909-6912
Number of pages4
JournalJournal of Biological Chemistry
Volume276
Issue number10
DOIs
StatePublished - Mar 9 2001

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Glycosylphosphatidylinositols
Macrophages
Plasmodium falciparum
Endocytosis
Membranes
Cell signaling
Protein-Tyrosine Kinases
Protein Kinase C
Glycerides
Poisons
Cell membranes
Mannose
Malaria
Phosphotransferases
Chemical activation
Carbohydrates
Cell Membrane
Cytokines

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Plasmodium falciparum Glycosylphosphatidylinositol-induced TNF-α Secretion by Macrophages is Mediated without Membrane Insertion or Endocytosis",
abstract = "The glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum are believed to contribute to the pathogenesis of malaria by inducing the secretion of proinflammatory cytokines by macrophages. Previous studies have shown that P. falciparum GPIs elicit toxic immune responses by protein tyrosine kinase (PTK)- and protein kinase C (PKC)-mediated cell signaling pathways, which are activated by the carbohydrate and acyl moieties of the intact GPIs, respectively. In this study, we show that induction of TNF-α by P. falciparum GPIs in macrophages is mediated by the recognition of the distal fourth mannose residue. This event is critical but not sufficient for the productive cell signaling; interaction by the acylglycerol moiety of GPIs is also required. These novel interactions are coupled to previously demonstrated PTK and PKC pathways, since the specific inhibitors of these kinases effectively blocked the GPI-induced TNF-α production. Surprisingly, sn-2 lyso-GPIs were also able to elicit TNF-α secretion. Contrary to the prevailing notion, GPIs are neither inserted to the plasma membranes nor endocytosized. Thus, this study defines the GPI structural requirements and reveals a novel mechanism for the outside-in activation of cell signaling by P. falciparum GPIs in inducing proinflammatory responses.",
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Plasmodium falciparum Glycosylphosphatidylinositol-induced TNF-α Secretion by Macrophages is Mediated without Membrane Insertion or Endocytosis. / Vijaykumar, Matam; Naik, Ramachandra S.; Gowda, Channe.

In: Journal of Biological Chemistry, Vol. 276, No. 10, 09.03.2001, p. 6909-6912.

Research output: Contribution to journalArticle

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