Characterization of cofactor activity for factor I: cleavage of complement C4 in human syncytiotrophoblast microvilli.
To coexist with complement, human tissues express membrane-integrated regulatory proteins that inhibit the activity of autologous complement on cell surfaces. Certain of these complement regulatory proteins act as obligatory cofactors for proteolytic inactivation of activated C4(C4b) by factor I. Extraembryonic tissues and in particular trophoblasts constitute an interface at risk from maternal complement during pregnancy. The present study examined syncytiotrophoblast plasma membrane (STM) cofactor activity for cleavage of immobilized methylamine-treated complement component C4(C4ma), a C4b analog by factor I. Membrane cofactor protein (MCP or CD46) provided most of the cofactor activity in STM preparations. Minor cofactor activity was derived from C4 binding protein that was firmly bound to STM. Cofactor activity for cleavage of C4ma at its two sites for factor I was enhanced at higher concentrations of STM and at lower concentrations cleavage at a C terminal site predominated. Soluble cofactor activity was present in STM preparations and was provided by 65 KDa, 55 KDa and 50 KDa soluble species of MCP that lacked amphiphilic properties. These results are consistent with a major role for MCP in regulation of C4 activity on the maternal-facing surfaces of extraembryonic tissues during human development. Soluble MCP may provide additional fluid phase complement regulatory activity in the maternotrophoblastic zone.
Vanderpuye
O A
OA
Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Indianapolis 46202.
Beville
C M
CM
McIntyre
J A
JA
D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D001792:Blood Platelets / Q000648:ultrastructure; D002462:Cell Membrane / Q000276:immunology; D003181:Complement C4 / Q000378:metabolism*; D017244:Complement Factor I / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007668:Kidney / Q000648:ultrastructure; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D008744:Methylamines / Q000494:pharmacology; D008871:Microvilli / Q000378:metabolism*; D008970:Molecular Weight; D010446:Peptide Fragments / Q000378:metabolism; D011247:Pregnancy; D012995:Solubility; D014327:Trophoblasts / Q000648:ultrastructure*
D000906:Antibodies; D015703:Antigens, CD; C497857:CD46 protein, human; D003181:Complement C4; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D008744:Methylamines; D010446:Peptide Fragments; C027451:methylamine; D017244:Complement Factor I