Stimulation of human neutrophils, monocytes, and platelets by modified C-reactive protein (CRP) expressing a neoantigenic specificity

Potempa, Lawrence A.; Zeller, Janice M.; Fiedel, Barry A.; Kinoshita, Carol M.; Gewürz, Henry

doi:10.1007/bf00915774

Cited by 71 publications

(47 citation statements)

References 38 publications

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“…Alternatively, mCRP may be also formed at sites of injury or infection as part of the activation of the acute inflammatory response. The present and previous findings lend strong experimental support to the hypothesis that conformationally altered forms of CRP such as mCRP display potent pro-inflammatory activities potentiating activated responses of neutrophils, monocytes, and platelets (43,57), whereas native CRP has activities mainly associated with the resolution of inflammation.…”

Section: Discussionsupporting

confidence: 84%

Loss of Pentameric Symmetry of C-Reactive Protein Is Associated with Promotion of Neutrophil-Endothelial Cell Adhesion

Zouki

Haas

Chan

et al. 2001

The Journal of Immunology

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The classic acute-phase reactant C-reactive protein (CRP) is a cyclic pentameric protein that diminishes neutrophil accumulation in inflamed tissues. When the pentamer is dissociated, CRP subunits undergo conformational rearrangement that results in expression of a distinctive isomer with unique antigenic and physicochemical characteristics (termed modified CRP (mCRP)). Recently, mCRP was detected in the wall of normal human blood vessels. We studied the impact and mechanisms of action of mCRP on expression of adhesion molecules on human neutrophils and their adhesion to human coronary artery endothelial cells. Both CRP and mCRP (0.1–200 μg/ml) down-regulated neutrophil l-selectin expression in a concentration-dependent fashion. Furthermore, mCRP, but not CRP, up-regulated CD11b/CD18 expression and stimulated neutrophil extracellular signal-regulated kinase activity, which was accompanied by activation of p21ras oncoprotein, Raf-1, and mitogen-activated protein kinase kinase. These actions of mCRP were sensitive to the mitogen-activated protein kinase kinase inhibitor PD98059. mCRP markedly enhanced attachment of neutrophils to LPS-activated human coronary artery endothelial when added together with neutrophils. This effect of mCRP was attenuated by an anti-CD18 mAb. Thus, loss of pentameric symmetry in CRP is associated with appearance of novel bioactivities in mCRP that enhance neutrophil localization and activation at inflamed or injured vascular sites.

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Section: Discussionsupporting

confidence: 84%

Loss of Pentameric Symmetry of C-Reactive Protein Is Associated with Promotion of Neutrophil-Endothelial Cell Adhesion

Zouki

Haas

Chan

et al. 2001

The Journal of Immunology

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“…The CRP concentrations were determined using high sensitivity turbidimetry technique (Bayer HealthCare, Advia 1650, NY, USA). Irreversible dissociation of purified CRP (mCRP) was obtained by acid-treatment (pH 2.0) of pentameric CRP prior to neutralization [19].…”

Section: Reagentsmentioning

confidence: 99%

“…Under these conditions in vitro, there is evidence that CRP undergoes structural changes with dissociation of its subunits [19,20]. These monomeric CRP subunits (mCRP) expose epitopes not present on pentameric CRP and display properties distinct from those of native CRP.…”

Section: Introductionmentioning

confidence: 99%

Solid-phase classical complement activation by C-reactive protein (CRP) is inhibited by fluid-phase CRP–C1q interaction

Sjöwall

Wetterö

Bengtsson

et al. 2007

Biochemical and Biophysical Research Communications

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C-reactive protein (CRP) interacts with phosphorylcholine (PC), Fc receptors, complement factor C1q and cell nuclear constituents, yet its biological roles are insufficiently understood.The aim was to characterize CRP-induced complement activation by ellipsometry. PC conjugated with keyhole limpet hemocyanin (PC-KLH) was immobilized to cross-linked fibrinogen. A low-CRP serum with different amounts of added CRP was exposed to the PCsurfaces. The total serum protein deposition was quantified and deposition of IgG, C1q, C3c, C4, factor H and CRP detected with polyclonal antibodies. The binding of serum CRP to PC-KLH dose-dependently triggered activation of the classical pathway. Unexpectedly, the activation was efficiently down-regulated at CRP levels >150 mg/L. Using radial immunodiffusion, CRP-C1q interaction was observed in serum samples with high CRP concentrations. We propose that the underlying mechanism depends on fluid-phase interaction between C1q and CRP. This might constitute another level of complement regulation, which has implications for systemic lupus erythematosus where CRP is often low despite flare-ups.

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“…neo-epitopes are preferentially capable of activating platelets, polymorphonuclear leucocytes, and monocytes in vitro, 8 bind various forms of lipoproteins 9 and contribute to complement activation. 10 CRP activates the classical pathway of complement when bound to appropriate ligands.…”

Section: Introductionmentioning

confidence: 99%

“…16 Unlike ligand-bound native CRP, mCRP was shown to be unable to induce depletion of haemolytic complement activity. 8 CRP efficiently activates the early components of the classical pathway (C1, C4, C2) but generates little C5-C9 consumption. 17 Surface-bound CRP decreases the alternative complement pathway C3-convertase and C5-convertase activities, inhibits the alternative amplification loop and reduces deposition of C3b and lysis by the lectin pathway.…”

Section: Introductionmentioning

confidence: 99%

Studies on the interactions between C‐reactive protein and complement proteins

et al. 2007

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Studies on the interactions between C-reactive protein and complement proteins IntroductionThe classical acute-phase reactant C-reactive protein (CRP) is a pentameric, disc-shaped serum protein.1 Its basic features are the control of inflammation, the stimulation of clearance of damaged cell and tissue components, and the initiation of repair functions.2 CRP shows calcium-dependent affinity for phosphate monoesters, such as phosphatidylcholine, but several other ligands of CRP have been characterized, including damaged cell membranes, small ribonucleoprotein particles, apoptotic cells and fibronectin. Native CRP can undergo subunit dissociation into individual monomeric units, for example upon association with negatively charged lipid monolayers. 4 This modified form of CRP can be produced in vitro by urea chelation, acid treatment, heating or direct immobilization of native CRP onto polystyrene.5 This modified form of CRP (mCRP) has reduced solubility and exhibits different electrophoretic characteristics as the result of a decrease of isoelectric point (pI) from 6Á4 to 5Á4. 6 The structural changes releasing CRP subunits from the pentamer are correlated with expression of a new antigenic reactivity and formation of neo-epitopes. 7 The forms of CRP expressing SummarySeveral studies have investigated the interactions between C-reactive protein (CRP) and various complement proteins but none of them took into consideration the different structural forms of CRP. The aim of our study was to investigate whether the different antigenic forms of CRP are able to bind C1q, to trigger activation of the C1 complex and to study the ability of the various CRP forms to bind complement factor H (FH) and C4b-binding protein (C4BP). Interactions between various CRP forms and complement proteins were analysed in enzyme-linked immunosorbent assay and surface plasmon resonance tests and activation of the C1 complex was followed in a reconstituted system using purified C1q, C1r and C1s in the presence of C1-INH. Native, ligand-unbound CRP activated the classical pathway weakly. After binding to phosphocholine, native CRP bound C1q and significantly activated C1. Native CRP complexed to phosphocholine did not bind the complement regulatory proteins FH and C4BP. After disruption of the pentameric structure of CRP, as achieved by urea-treatment or by site-directed mutagenesis, C1q binding and C1 activation further increased and the ability of CRP to bind complement regulatory proteins was revealed. C1q binds to CRP through its globular head domain. The binding sites on CRP for FH and C4BP seemed to be different from that of C1q. In conclusion, in parallel with the increase in the C1-activating ability of different CRP structural variants, the affinity for complement regulatory proteins also increased, providing the biological basis for limitation of excess complement activation.

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Stimulation of human neutrophils, monocytes, and platelets by modified C-reactive protein (CRP) expressing a neoantigenic specificity

Cited by 71 publications

References 38 publications

Loss of Pentameric Symmetry of C-Reactive Protein Is Associated with Promotion of Neutrophil-Endothelial Cell Adhesion

Loss of Pentameric Symmetry of C-Reactive Protein Is Associated with Promotion of Neutrophil-Endothelial Cell Adhesion

Solid-phase classical complement activation by C-reactive protein (CRP) is inhibited by fluid-phase CRP–C1q interaction

Studies on the interactions between C‐reactive protein and complement proteins

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