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 penta meric protein that diminishes neutrophil accumulation in inflamed tissues. When the pentamer is dissociated, CRP subunits undergo conformational rearr angement that results in expression of a distinctive isomer with unique ant igenic and physicochemical characteristics (termed modified CRP (mCRP)). Re cently, mCRP was detected in the wall of normal human blood vessels. We stu died 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 mug/ml) down-regulated neutro phil L-selectin expression in a concentration-dependent fashion. Furthermor e, mCRP, but not CRP, up-regulated CD11b/CD18 expression and stimulated neu trophil extracellular signal-regulated kinase activity, which was accompani ed by activation of p21(ras) oncoprotein, Raf-1, and mitogen-activated prot ein kinase kinase. These actions of mCRP were sensitive to the mitogen-acti vated protein kinase kinase inhibitor PD98059. mCRP markedly enhanced attac hment of neutrophils to LPS-activated human coronary artery endothelial whe n 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 localiza tion and activation at inflamed or injured vascular sites.