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The Glycosyl-Inositol-Phosphate and Dimyristoylglycerol Moieties of the Glycosylphosphatidylinositol Anchor of the Trypanosome Variant-Specific Surface Glycoprotein Are Distinct Macrophage-Activating Factors¹

Stefan Magez^2,*, Benoît Stijlemans^*, Magdalena Radwanska, Etienne Pays, Michael A. J. Ferguson and Patrick De Baetselier^*

^* Laboratory of Cellular Immunology, Flanders Interuniversity Institute for Biotechnology, Free University of Brussels (Vrije Universiteit Brussel), and Department of Molecular Biology, Free University of Brussels (Université Libre de Bruxelles), Brussels, Belgium; and Department of Biochemistry, The University Dundee, Scotland, United Kingdom

The TNF--inducing capacity of different trypanosome components was analyzed in vitro, using as indicator cells a macrophage cell line (2C11/12) or peritoneal exudate cells from LPS-resistant C₃H/HeJ mice and LPS-sensitive C₃H/HeN mice. The variant-specific surface glycoprotein (VSG) was identified as the major TNF--inducing component present in trypanosome-soluble extracts. Both soluble (sVSG) and membrane-bound VSG (mfVSG) were shown to manifest similar TNF--inducing capacities, indicating that the dimyristoylglycerol (DMG) compound of the mfVSG anchor was not required for TNF- triggering. Detailed analysis indicated that the glycosyl-inositol-phosphate (GIP) moiety was responsible for the TNF--inducing activity of VSG and that the presence of the GIP-associated galactose side chain was essential for optimal TNF- production. Furthermore, the results showed that the responsiveness of macrophages toward the TNF--inducing activity of VSG was strictly dependent on the activation state of the macrophages, since resident macrophages required IFN- preactivation to become responsive. Comparative analysis of the ability of both forms of VSG to activate macrophages revealed that mfVSG but not sVSG stimulates macrophages toward IL-1 secretion and acquisition of LPS responsiveness. The priming activity of mfVSG toward LPS responsiveness was also demonstrated in vivo and may be relevant during trypanosome infections, since Trypanosoma brucei-infected mice became gradually LPS-hypersensitive during the course of infection. Collectively, the VSG of trypanosomes encompasses two distinct macrophage-activating components: while the GIP moiety of sVSG mediates TNF- induction, the DMG compound of the mfVSG anchor contributes to IL-1 induction and LPS sensitization.