THE GLYCOSYL-INOSITOL-PHOSPHATE AND DIMYRISTOYLGLYCEROL MOIETIES OF THE GLYCOSYLPHOSPHATIDYLINOSITOL ANCHOR OF THE TRYPANOSOME VARIANT-SPECIFIC SURFACE GLYCOPROTEIN ARE DISTINCT MACROPHAGE-ACTIVATING FACTORS
S. Magez et al., THE GLYCOSYL-INOSITOL-PHOSPHATE AND DIMYRISTOYLGLYCEROL MOIETIES OF THE GLYCOSYLPHOSPHATIDYLINOSITOL ANCHOR OF THE TRYPANOSOME VARIANT-SPECIFIC SURFACE GLYCOPROTEIN ARE DISTINCT MACROPHAGE-ACTIVATING FACTORS, The Journal of immunology, 160(4), 1998, pp. 1949-1956
The TNF-alpha-inducing capacity of different trypanosome components wa
s analyzed in vitro, using as indicator cells a macrophage cell line (
2C11/12) or peritoneal exudate cells from LPS-resistant C3H/HeJ mice a
nd LPS-sensitive C3H/HeN mite. The variant-specific surface glycoprote
in (VSG) was identified as the major TNF-alpha-inducing component pres
ent in trypanosome-soluble extracts. Both soluble (sVSG) and membrane-
bound VSG (mfVSG) were shown to manifest similar TNF-alpha-inducing ca
pacities, indicating that the dimyristoylglycerol (DMG) compound of th
e mfVSG anchor was not required for TNF-alpha triggering. Detailed ana
lysis indicated that the glycosyl-inositol-phosphate (GIP) moiety was
responsible for the TNF-alpha-inducing activity of VSG and that the pr
esence of the GIP-associatcd galactose side chain was essential for op
timal TNF-alpha production. Furthermore, the results showed that the r
esponsiveness of macrophages toward the TNF-alpha-inducing activity of
VSG was strictly dependent on the activation state of the macrophages
, since resident macrophages required IFN-gamma preactivation to becom
e responsive, Comparative analysis of the ability of both forms of VSG
to activate macrophages revealed that mfVSG but not sVSG stimulates m
acrophages toward IL-1 alpha secretion and acquisition of LPS responsi
veness. The priming activity of mfVSG toward LPS responsiveness was al
so demonstrated in vivo and may be relevant during trypanosome infecti
ons, since Trypanosoma brucei-infected mice became gradually LPS-hyper
sensitive during the course of infection. Collectively, the VSG of try
panosomes encompasses two distinct macrophage-activating components: w
hile the GIP moiety of sVSG mediates TNF-alpha induction, the DMG comp
ound of the mfVSG anchor contributes to IL-1 alpha induction and LPS s
ensitization.