Complement regulatory protein C1 inhibitor binds to selectins and interferes with endothelial-leukocyte adhesion.
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 Lewis(x)-related moieties and therefore binds to selectin adhesion molecules. We demonstrated that plasma C1INH does express sialyl Lewis(x)-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 micro g/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.
Cai
Shenghe
S
Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
Davis
Alvin E
AE
D000818:Animals; D016466:CHO Cells; D002236:Carbohydrate Conformation; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D003172:Complement C1 / Q000378:metabolism*; D003174:Complement C1 Inactivator Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D050718:Complement C1 Inhibitor Protein; D006224:Cricetinae; D019040:E-Selectin / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016256:Lewis X Antigen / Q000096:biosynthesis / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D015843:Serpins / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D020298:U937 Cells
D003172:Complement C1; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D019040:E-Selectin; D016256:Lewis X Antigen; D019007:P-Selectin; D011480:Protease Inhibitors; C469952:SERPING1 protein, human; D015843:Serpins