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 (TNF) and interferon gamma (IFNγ) 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.

HIF‐dependent induction of apical CD55 coordinates epithelial clearance of neutrophils

“…CD55 has historically been viewed as a regulator of innate immunity through its regulation of the complement pathway (44). CD55 is expressed in most tissues exposed to serum components, and CD55 expression has been shown, in human endothelial systems, to be augmented in response to numerous inflammatory stimuli, including cytokines (45,46) and conditions found within the hypoxic microenvironment (e.g., VEGF) (47). Whereas baseline expression of CD55 in epithelium is sporadic, marked increases in expression are seen in areas of intestinal metaplasia or inflammation (48,49), particularly in patients with ulcerative colitis (50).…”

Cytokine-mediated up-regulation of CD55 and CD59 protects human hepatoma cells from complement attack

“…For other cell lines, such as the colonic adenocarcinoma cell line HT29, CD55 expression increased upon exposure to AP response cytokines, but not IFN-g , and CD46 expression was increased following addition of IL-1b [27,28,31,39]. DAF expression was also found to increase on cells derived from lung carcinomas or primary endothelial cells following incubation with TNF-a or IFN-g [37,38]. Gasque et al [40] found an increase in CD59 on oligodendroglioma cells following incubation with IFN-g.…”

Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution

“…In the past, CD55 has been viewed as a regulator of innate immunity through its regulation of the complement pathway (33). CD55 is expressed in most tissues exposed to serum components, and CD55 expression has been shown, in human endothelial systems, to be augmented in response to numerous inflammatory stimuli, including cytokines (34,35). Moreover, PMN express CD55 (36), although less is known about the potential contribution of PMN CD55.…”