Regulation of complement classical pathway by association of C4b-binding protein to the surfaces of SK-OV-3 and Caov-3 ovarian adenocarcinoma cells.
The role of fluid-phase regulators of complement is to inhibit excessive complement activation and maintain homeostasis in blood. By binding to and inactivating complement components on cell surfaces, they can also protect autologous cells from complement-mediated cytotoxicity and phagocytosis. In this study, we wanted to find out whether C4b-binding protein (C4bp), a fluid-phase regulator of the classical complement pathway, could directly bind to cell surfaces in a functionally active form. After screening several malignant cell lines, we observed that the ovarian adenocarcinoma cell lines SK-OV-3, Caov-3, and SW626 were capable of binding C4bp. Binding tests with recombinant deletion mutants suggested that the primary binding site on C4bp is located on the alpha-chain complement control protein 4 domain. Functional tests showed that tumor cell-bound C4bp retained its cofactor activity for factor I-mediated inactivation of C4b, thus increasing the control of classical complement pathway activation on the surfaces of these cells. These results demonstrate a novel mechanism of complement regulation on cell surfaces, particularly on those of malignant ovarian tumor cells.
Holmberg
M T
MT
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.
Blom
A M
AM
Meri
S
S
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001666:Binding Sites, Antibody; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism*; D017244:Complement Factor I / Q000378:metabolism; D003169:Complement Inactivator Proteins; D003171:Complement Pathway, Classical / Q000276:immunology*; D005260:Female; D006023:Glycoproteins; D006801:Humans; D007106:Immune Sera / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism*; D010449:Peptide Mapping; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D007106:Immune Sera; D007457:Iodine Radioisotopes; D011951:Receptors, Complement; D011994:Recombinant Proteins; D015935:Complement C4b; D017244:Complement Factor I