EFFECT OF HUMAN C-REACTIVE PROTEIN ON CHEMOKINE AND CHEMOTACTIC FACTOR-INDUCED NEUTROPHIL CHEMOTAXIS AND SIGNALING

C-reactive protein (CRP) is a unique serum pentraxin and the prototype acute phase reactant, CRP is a ligand for specific receptors on phago cytic leukocytes, and mediates activation reactions of monocytes/macro phages, but inhibits the respiratory burst of neutrophils (PMN), Since CRP selectively accumulates at inflammatory sites in which IL-8 is al so produced, we tested the effects of CRP on the responsiveness of PMN to IL-8 and the bacterial chemotactic peptide, FMLP-phenylalanine (FM LPP). Purified human CRP inhibited the chemotactic response of PMN to IL-8 and FMLPP. A mouse IgM mAb that was generated against the leukocy te CRP receptor (CRP-R) also inhibited the chemotactic response. Incub ation of purified CRP with activated PMN generated CRP-derived peptide s that also inhibited chemotaxis, A synthetic CRP peptide (residues 27 -38) that binds to the CRP-R had weak chemotactic activity, whereas tw o other CRP synthetic peptides (residues 174-185 and 191-205) inhibite d chemotaxis of PMNs to both IL-8 and FMLPP, CRP did not alter recepto r-specific binding of IL-8, but exerted its effect at the level of sig naling. CRP augmented both IL-8- and FMLPP-induced mitogen-activated p rotein kinase (extracellular signal-regulated kinase-2) activity. CRP at acute phase levels increased both agonist-induced and noninduced ph osphatidylinositol-3 kinase activity. The results suggest a role for C RP as a regulator of leukocyte infiltration at inflammatory sites.