title: Induction of decay-accelerating factor by cytokines or the membrane-attack complex protects vascular endothelial cells against complement deposition.
abstract: Vascular endothelium is continuously exposed to complement-mediated challenge, and this is enhanced during inflammation. Although the complement-regulatory proteins decay-accelerating factor (DAF), CD59, and membrane cofactor protein (MCP) protect endothelial cells (ECs) against complement-mediated injury, the control of their expression and relative contributions to vascular protection is unclear. We explored the hypothesis that mechanisms exist which induce upregulation of complement-regulatory proteins on ECs to maintain vascular function in inflammation. Tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) each increased DAF expression but not CD59 or MCP expression, and a combination of these cytokines was more potent than either alone. Cytokine-induced expression depended on increased DAF mRNA and de novo protein synthesis and was maximal by 72 hours. In addition, assembly of the membrane-attack complex (MAC) on ECs induced a 3-fold increase in DAF expression, and this was enhanced by cytokines. DAF upregulation was not inhibited by protein kinase C (PKC) antagonists. The increase in DAF was functionally relevant since it reduced complement 3 (C3) deposition by 40%, and this was inhibited by an anti-DAF monoclonal antibody. These observations indicate that upregulation of DAF expression by cytokines or MAC may represent an important feedback mechanism to maintain the integrity of the microvasculature during subacute and chronic inflammatory processes involving complement activation.
authors.affiliation: British Heart Foundation (BHF) Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College School of Technology and Medicine, Hammersmith Hospital, London, UK. jmason@rpms.ac.uk
authors.forename: J C
authors.initials: JC
authors.lastname: Mason
authors.forename: H
authors.initials: H
authors.lastname: Yarwood
authors.forename: K
authors.initials: K
authors.lastname: Sugars
authors.forename: B P
authors.initials: BP
authors.lastname: Morgan
authors.forename: K A
authors.initials: KA
authors.lastname: Davies
authors.forename: D O
authors.initials: DO
authors.lastname: Haskard
mesh_terms: D015703:Antigens, CD / Q000502:physiology; D018958:CD55 Antigens / Q000502:physiology*; D018957:CD59 Antigens / Q000502:physiology; D002478:Cells, Cultured; D003167:Complement Activation; D003169:Complement Inactivator Proteins / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000502:physiology; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C497857:CD46 protein, human; D018958:CD55 Antigens; D018957:CD59 Antigens; D003169:Complement Inactivator Proteins; D016207:Cytokines; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins