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*
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.
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