C-Reactive Protein Upregulates Complement-Inhibitory Factors in Endothelial Cells

Abstract

Background-Because complement-mediated vascular injury participates in atherosclerosis and C-reactive protein (CRP) can activate the complement cascade, we sought to determine whether CRP affects the expression of the protective complement-inhibitory factors on the cell surface of endothelial cells (ECs). Methods and Results-Human coronary artery or human saphenous vein ECs were incubated with CRP (0 to 100 g/mL, 0 to 72 hours), and the expression of the complement-inhibitory proteins decay-accelerating factor (DAF), membrane cofactor protein (CD46), and CD59 were measured by flow cytometry. Incubation with CRP resulted in a significant increase in the expression of all 3 proteins. CRP-induced upregulation of DAF required increased steady-state mRNA and de novo protein synthesis. The increased expression of complement-inhibitory proteins was functionally effective, resulting in significant reduction of complement-mediated lysis of antibody-coated human saphenous vein ECs. Conclusions-These observations provide evidence for a possible protective role for CRP in atherogenesis. Key Words: endothelium Ⅲ atherosclerosis Ⅲ proteins T he inflammatory marker C-reactive protein (CRP) represents one of the strongest independent predictors of vascular death in several settings. 1,2 Originally suggested to play the role of a biomarker, CRP seems to be a mediator of atherosclerosis. 3 CRP elicits a multitude of effects on endothelial biology that favor a proatherosclerotic phenotype, such as decreasing NO release, 4 upregulating adhesion molecules, 5 stimulating vascular smooth muscle cell proliferation and migration, 6 and activating the complement system. 7 The complement system is a complex cascade of enzymes and regulatory proteins that normally participate in host defenses against microorganisms via opsonization, chemoattraction of leukocytes, cell lysis, and cell activation. 8 However, complement activation also has been proposed to participate in both the initiation and progression of atherosclerosis. 9 This is supported by the presence of activated complement components in atherosclerotic plaques, such as the membrane attack complex (MAC, C5b-9), which promotes cellular activation, upregulates adhesion molecules, stimulates chemokine secretion, and can cause cell lysis. 10 To prevent host cell damage, nucleated cells have developed membrane-bound regulators of complement activation. Among these regulatory proteins is decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), which binds to and facilitates the degradation of C3b and C4b, and CD59, which inhibits C5b-9. 11 DAF prevents the formation and accelerates the decay of the C3 and C5 convertases that act early within the complement cascade, 11 functioning to maintain vascular integrity as a key protector against complement-mediated cell lysis. 12 The classical pathway of complement may be activated by CRP bound to enzymatically degraded low-density lipoprotein. 13 The effect of CRP on the expression of complementinhibitory factors is unknow...

Neointimal formation is reduced after arterial injury in human crp transgenic mice

“…CRP confers protection against autoimmune diseases: CRPtg are relatively insensitive to murine systemic lupus [41], and experimental allergic encephalomyelitis [42]. Furthermore, CRP upregulated the expression of complement inhibitory factors on endothelial cells [43], suggesting that CRP may protect from complement-mediated vascular injury implicated in intimal hyperplasia [44].…”

The Classical and Regulatory Functions of C1q in Immunity and Autoimmunity

“…The difference between CRP and immune complexes as C1q ligands is that CRP but not immune complexes also binds factor H (71). CRP also up-regulates complement inhibitory proteins such as CD59, decay-accelerating protein (DAF) and membrane co-factor protein (MCP) on target cells (72). These mechanisms act to limit complement activation within the early components of the cascade which causes effective opsonization with C3 and C4 fragments for phagocytosis while minimizing the formation of anaphylatoxins and membrane-lytic complement complexes and therefore minimizing tissue inflammation and damage (71)(72)(73).…”

“…CRP also up-regulates complement inhibitory proteins such as CD59, decay-accelerating protein (DAF) and membrane co-factor protein (MCP) on target cells (72). These mechanisms act to limit complement activation within the early components of the cascade which causes effective opsonization with C3 and C4 fragments for phagocytosis while minimizing the formation of anaphylatoxins and membrane-lytic complement complexes and therefore minimizing tissue inflammation and damage (71)(72)(73). CRP and another pentraxin serum amyloid P component (SAP) both bind to chromatin on AC and recruit C1q to elicit complement activation (27,73).…”

“…CRP can limit the activation of late complement components on AC by binding to factor H which enhances C3b cleavage into iC3b (71). It also up-regulates surface expression of DAF, MCP and CD59 on host cells although whether this occurs on AC is unclear (72). CRP is an acute phase protein and is likely to be significant under inflammatory conditions when plasma complement infiltrates peripheral tissues (119).…”

C-reactive protein and the risk of developing type 2 diabetes in Aboriginal Australians

“…C-reactive protein (CRP) is an inflammatory marker produced and released by the liver under the stimulation of cytokines such as tumor necrosis factor-a and interleukins 1 and 6. It might affect the process of the atherothrombosis [2] and [3]. It has emerged as a powerful risk marker for cardiovascular disease [4], [5] and [6].…”