We recently showed that the
acute-phase protein alpha(1)-acid glycoprotein (AGP) induces rises in cytosolic
calcium concentration, [Ca(2+)](i,) in neutrophils through
sialic acid dependent interactions with the neutrophil receptors siglec-5 and/or siglec-14. Whereas both siglec-5 and siglec-14 have a relatively broad specificity for sialylated
oligosaccharide structures, including both structures with terminal alpha2-3 or alpha2-6 linked
sialic acid, there is a markedly reduced affinity to the fucosylated
epitope sialyl Lewis x (
SLe(x)). Increased fucosylation, leading to increased expression of
SLe(x) on AGP is commonly associated with inflammatory conditions. In the present study, we investigated whether an increased
SLe(x) expression would affect the Ca(2+)-mobilizing effect of AGP. AGP with elevated
fucose content isolated from patients with untreated chronic joint
inflammation showed a decreased [Ca(2+)](i) modulatory effect on neutrophils compared to normally fucosylated AGP. Furthermore a hyperfucosylated AGP form produced by in vitro fucosylation, that consequently had an elevated expression of
SLe(x), could not elicit a [Ca(2+)](i) increase in neutrophils. The role of the
carbohydrate portion of AGP in modulating neutrophil responses was further strengthened by showing that synthetic
glycoconjugates carrying
oligosaccharides with terminal alpha2-3 or alpha2-6 linked
sialic acid were able to mimic the Ca(2+)-mobilizing effect of AGP whereas a synthetic
glycoconjugate carrying
SLe(x) was not. Based on these data, we conclude that increased fucosylation can alter the ability of AGP to induce neutrophil signalling and further supports an important role of the
oligosaccharide chains of AGP in the modulation of leukocyte functions during an inflammatory process.