The aim of this review is to summarize the research efforts of the last two decades with respect to (i) the determination and characterization of the changes in glycosylation of AGP under various physiological and pathological states; and (ii) the effects of such changes on its possible anti-inflammatory functions. It will become clear that the heterogeneity observed in the glycosylation of AGP in serum, represents various so-called glycoforms of AGP, of which the relative amounts are strictly determined by the (patho) physiological conditions.
ƒ¿1-Acid glycoprotein (AGP) is an acute-phase glycopro-tein with five .N linked glycans, exhibiting substantial heteroge-neity in their structures. This heterogeneity results from the presence in plasma of various distinct AGP glycoforms of which the plasma levels, and thus the relative occurrence of these glycoforms, are strictly dependent on the pathophysi-ological condition determined by cytokines and hormones. These humoral factors induce changes in the glycosylation process of the parenchymal liver cells, which are independent of the rate of synthesis of the AGP aglycon. Results are reviewed regarding the characterization and regulation of the changes in glycosylation of AGP under various physiological and pathological states, as well as the possible anti-inflammatory effects of different AGP glycoforms.
The effect of estrogen on the glycosylation of alpha 1-acid glycoprotein was studied in women using oral contraceptives and in male-to-female transsexuals receiving oral or transdermal estrogen treatment. Oral estrogen treatment induced an increase in degree of branching and a decrease in fucosylation and sialyl Lewis x expression on alpha 1-acid glycoprotein compared to individuals receiving no estrogens or transdermal estrogen treatment. The effect on the glycosylation of alpha 1-acid glycoprotein was less in the male-to-female transsexuals receiving oral estrogens in combination with cyproterone acetate, a blocker of the androgen receptor with progestagen-like effects. This was of comparable magnitude as in women using oral contraceptives containing both estrogen and progestagen. We conclude that oral estrogens have an identical effect on the hepatic glycosylation of alpha 1-acid glycoprotein in both males and females and that progestagen reduces this effect. These results show that oral estrogens induce an effect on the glycosylation of alpha 1-acid glycoprotein opposite to that induced by inflammation. Oral estrogens can therefore modulate the glycosylation dependent inflammatory actions of alpha 1-acid glycoprotein, while this is not the case with transdermal estrogens. In all likelihood, estrogen receptors on the hepatocyte must play a significant role in the observed effect.
Acute and chronic inflammation-induced expression of sialyl LewisX has already been shown to occur on alpha1-acid glycoprotein. We now demonstrate that this phenomenon is not restricted to alpha1-acid glycoprotein but also occurs on two other acute-phase proteins. ie on alpha1-antichymotrypsin and on haptoglobin. The level of expression of sialyl LewisX on these proteins was lower than on alpha1-acid glycoprotein, in all likelihood because alpha1-acid glycoprotein is the only acute-phase protein containing tetraantennary glycans. No expression of sialyl LewisX was detectable on alpha1-protease inhibitor, a protein with a high diantennary glycan content. Non-sialylated LewisX was not detectable on these major acute-phase proteins in any of the conditions studied. This indicates that the majority of the a3-linked fucose residues are present as sialyl LewisX on alpha1-acid glycoprotein, alpha1-antichymotrypsin and haptoglobin. The absolute contribution to the total phenotype in plasma of protein containing this determinant in a multivalent form was highest for alpha1-acid glycoprotein. This leads us to propose that alpha1-acid glycoprotein is, among the acute-phase proteins studied, the one with the highest potential for interference with the extravasation of leukocytes by binding to the selectins.
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