Complement Regulatory Protein C1 Inhibitor Binds to Selectins and Interferes with Endothelial-Leukocyte Adhesion

Abstract

C1 inhibitor (C1INH), a member of the serine proteinase inhibitor (serpin) family, is an inhibitor of proteases in the complement system, the contact system of kinin generation, and the intrinsic coagulation pathway. It is the most heavily glycosylated plasma protein, containing 13 definitively identified glycosylation sites as well as an additional 7 potential glycosylation sites. C1INH consists of two distinct domains: a serpin domain and an amino-terminal domain. The serpin domain retains all the protease-inhibitory function, while the amino-terminal domain bears most of the glycosylation sites. The present studies test the hypothesis that plasma C1INH bears sialyl Lewisx-related moieties and therefore binds to selectin adhesion molecules. We demonstrated that plasma C1INH does express sialyl Lewisx-related moieties on its N-glycan as detected using mAb HECA-452 and CSLEX1. The data also show that plasma C1INH can bind to P- and E-selectins by FACS and immunoprecipitation experiments. In a tissue culture model of endothelial-leukocyte adhesion, C1INH showed inhibition in a dose-dependent manner. Significant inhibition (>50%) was achieved at a concentration of 250 μg/ml or higher. This discovery may suggest that C1INH plays a role in the endothelial-leukocyte interaction during inflammation. It may also provide another example of the multifaceted anti-inflammatory effects of C1INH in various animal models and human diseases.

C1 Inhibitor-Mediated Protection from Sepsis

“…Combined with our previous observations in LPS-induced endotoxin shock and in TNF-␣-induced leukocyte rolling (39,44,61,62), and other published studies (26,27), the studies described in this work demonstrate that C1INH exerts its antibacterial and anti-inflammatory functions via several different mechanisms. These include, in addition to complement and contact system inhibition, the direct interaction of C1INH with endotoxin LPS (and with LPS-containing bacteria) and the inhibition of selectin-mediated leukocyte rolling (61,62).…”

The role of the complement and contact systems in the dextran sulfate sodium-induced colitis model: the effect of C1 inhibitor in inflammatory bowel disease

“…We have demonstrated that C1INH plays a direct role in modulating leukocyte adhesion in acute inflammation and intestinal ischemia and reperfusion models (4,5,26). C1INH binds to selectins, interferes with leukocyte-endothelial adhesion, and suppresses leukocyte transmigration across the endothelium (4,5). This activity is not related to its protease-inhibitory function because the reactive center-cleaved inactive form is as potent as the native form.…”

“…The treatment with C1INH in WT mice reversed the elevated tissue MPO levels in response to DSS, consequently limiting the tissue damage, and suppressed the development of the DSS-induced colitis. We have demonstrated that C1INH plays a direct role in modulating leukocyte adhesion in acute inflammation and intestinal ischemia and reperfusion models (4,5,26). C1INH binds to selectins, interferes with leukocyte-endothelial adhesion, and suppresses leukocyte transmigration across the endothelium (4,5).…”

Expression of complement components and inhibitors on platelet microparticles

“…C1-INH can inhibit classical pathway complement activation by binding to C1r and C1s. It also binds to P-and E-selectins and interferes with leukocyte adhesion [41]. Since its anti proteolytic activity appears to be preserved after binding to P-selectin, C1-INH expression on PMP may limit the generation of C3a and C5a [42,43].…”