title: gC1qR/p33 serves as a molecular bridge between the complement and contact activation systems and is an important catalyst in inflammation.
abstract: The receptor for the globular heads of C1q, gC1qR/p33, is a ubiquitously expressed protein, which is distributed both intracellularly and on the cell-surface protein. In addition to C1q, this molecule also is able to bind several other biologically important plasma ligands, including high-molecular-weight kininogen (HK), factor XII (FXII), and multimeric vitronectin. Previous studies have shown that incubation of FXII, prekallikrein, and HK with gC1qR leads to a zinc-dependent and FXII-dependent conversion of prekallikrein to kallikrein, a requisite for kinin generation. In addition, these studies showed that normal plasma, but not plasma deficient in FXII, PK, or HK, activate upon binding to endothelial cells (EC), and that this activation could be inhibited by antibody to gClqR. In these studies, we show that incubation of serum with microtiter plate bound gC1qR results in complement activation, as evidenced by the binding and activation of C1 and generation of C4d. However, neither Clq-deficient serum nor a truncated form of gC1qR (gC1qRA74-96), supported complement activation. Taken together, the data strongly suggest that at sites of inflammation, such as vasculitis and atherosclerosis, where gC1qR as well as its two important plasma ligands, C1q and HK, have been shown to be simultaneously present, soluble or cell-surface-expressed gC1qR may contribute to the inflammatory process by modulating complement activation, kinin generation, and perhaps even initiation of clotting via the contact system. Based on these and other published data, we propose a model of inflammation in which atherogenic factors (e.g., immune complexes, virus, or bacteria) are perceived not only to convert the endothelium into a procoagulant and proinflammatory surface, but also to induce enhanced expression of cell surface molecules such as gC1qR. Enhanced expression of gC1qR in turn leads to: (i) high-affinity C1q binding and cell production of proinflammatory factors, and (ii) high-affinity HK binding and facilitation of the assembly of contact activation proteins leading to generation of bradykinin and possibly coagulation through activation of FXI.
authors.affiliation: Department of Medicine, SUNY at Stony Brook, Stony Brook, NY 11794, USA.
authors.forename: Berhane
authors.initials: B
authors.lastname: Ghebrehiwet
authors.forename: Claudia
authors.initials: C
authors.lastname: CebadaMora
authors.forename: Lee
authors.initials: L
authors.lastname: Tantral
authors.forename: Jolyon
authors.initials: J
authors.lastname: Jesty
authors.forename: Ellinor I B
authors.initials: EI
authors.lastname: Peerschke
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D003167:Complement Activation / Q000502:physiology*; D015922:Complement C1q / Q000276:immunology*; D006461:Hemolysis; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology
chemical_list: C087299:C1QBP protein, human; D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D011993:Recombinant Fusion Proteins; D015922:Complement C1q