Glycosylphosphatidylinositol toxin of Trypanosoma brucei regulates IL-1 alpha and TNF-alpha expression in macrophages by protein tyrosine kinase mediated signal transduction.
A purified, structurally defined glycosylphosphatidylinositol (GPI) derived from the Variant Surface Glycoprotein (VSG) of Trypanosoma brucei, and its biosynthetic precursor P2, was able at submicromolar concentrations to regulate cytokine expression when added directly as pharmacological agonist to host macrophages, by activation of an endogenous protein tyrosine-kinase (PTK) mediated signal transduction pathway. GPI induces rapid onset tyrosine phosphorylation of multiple intracellular substrates, within minutes of addition to LPS-nonresponsive cells, followed shortly thereafter by IL-1 alpha secretion. The PTK antagonists genistein and tyrphostin inhibit both tyrosylphosphorylation and cytokine expression. A monoclonal antibody to GPI also blocks IL-1 alpha induction by total parasite extracts. Thus, as in malaria infection, GPI may induce the cytokine excess causing certain pathological states associated with trypanosomiasis.
Tachado
S D
SD
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Schofield
L
L
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D015870:Gene Expression / Q000187:drug effects; D017261:Glycosylphosphatidylinositols / Q000302:isolation & purification / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis*; D007700:Kinetics; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014346:Trypanosoma brucei brucei; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000302:isolation & purification / Q000494:pharmacology*
D017261:Glycosylphosphatidylinositols; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D014643:Variant Surface Glycoproteins, Trypanosoma; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases