Loss of pentameric symmetry of C-reactive protein is associated with promotion of neutrophil-endothelial cell adhesion.
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 microg/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 p21(ras) 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.
Zouki
C
C
Research Center, Maisonneuve-Rosemont Hospital and Department of Medicine, University of Montréal, Montréal, Québec, Canada.
Haas
B
B
Chan
J S
JS
Potempa
L A
LA
Filep
J G
JG
D002097:C-Reactive Protein / Q000737:chemistry* / Q000502:physiology; D018821:CD18 Antigens / Q000032:analysis; D002448:Cell Adhesion; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1; D016177:Macrophage-1 Antigen / Q000032:analysis; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology
D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D002097:C-Reactive Protein; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human