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) de rived from the Variant Surface Glycoprotein (VSG) of Trypanosoma bruce i, and its biosynthetic precursor P2, was able at submicromolar concen trations to regulate cytokine expression when added directly as pharma cological agonist to host macrophages, by activation of an endogenous protein tyrosine-kinase (PTK) mediated signal transduction pathway. GP I induces rapid onset tyrosine phosphorylation of multiple intracellul ar substrates, within minutes of addition to LPS-nonresponsive cells, followed shortly thereafter by IL-1 alpha secretion. The PTK antagonis ts genistein and tyrphostin inhibit both tyrosylphosphorylation and cy tokine 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. (C) 1994 Academic Press, Inc.