α1-Antichymotrypsin Present in Therapeutic C1-Inhibitor Products Competes with Selectin-Sialyl LewisX Interaction.
Thromb Haemost
; 118(12): 2134-2144, 2018 Dec.
Article
em En
| MEDLINE
| ID: mdl-30453343
ABSTRACT
BACKGROUND:
C1-inhibitor (C1-inh) therapeutics can reduce neutrophil activity in various inflammatory conditions. This 'novel' anti-inflammatory effect of C1-inh is attributed to the tetrasaccharide sialyl LewisX (SLeX) present on its N-glycans. Via SLeX, C1-inh is suggested to interact with selectins on inflamed endothelium and prevent neutrophil rolling. However, C1-inh products contain plasma glycoprotein α1-antichymotrypsin (ACT) as a co-purified protein impurity.OBJECTIVE:
This article investigates the contribution of ACT to the effects observed with C1-inh. MATERIALS ANDMETHODS:
We have separated C1-inh and ACT from a therapeutic C1-inh preparation and investigated the influence of these proteins on SLeX-selectin interactions in a specific in vitro model, which makes use of rolling of SLeX-coated beads on immobilized E-selectin.RESULTS:
We find that ACT and not C1-inh, shows a clear sialic acid-dependent interference in SLeX-selectin interactions, at concentrations present in C1-inh therapeutics. Furthermore, we do not find any evidence of SLeX on C1-inh using either Western blotting with anti-SLeX antibodies (CSLEX1 and KM93) or by mass spectrometric analysis of N-glycans. C1-inh reacts weakly to antibody HECA-452, which detects a broad range of selectin ligands, but ACT gives a much stronger signal, suggesting the presence of a selectin ligand on ACT.CONCLUSION:
The 'novel' anti-inflammatory effects of C1-inh are unlikely due to SLeX on C1-inh and can in fact be due to SLeX-like glycans on ACT, present in C1-inh products. In view of our results, it is important to assess the role of ACT in vivo and revisit past studies performed with commercial C1-inh.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligossacarídeos
/
Endotélio Vascular
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Proteína Inibidora do Complemento C1
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Anti-Inflamatórios
/
Neutrófilos
Limite:
Humans
Idioma:
En
Revista:
Thromb Haemost
Ano de publicação:
2018
Tipo de documento:
Article