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The prototypic acute phase reactant C-reactive protein CRP is not only a marker but also a potential contributor to inflammatory diseases CRP exists as the circulating native pentameric CRP pCRP and the monomeric isoform mCRP formed as a result of a dissociation process of pCRP mCRP is highly pro-inflammatory but pCRP is not The mechanism of pro-inflammatory action of mCRP is unclear We studied the role of integrins in pro-inflammatory action of mCRP Docking simulation of interaction between mCRP and integrin v 3 predicted that mCRP binds to v 3 well We found that mCRP actually bound to integrins v 3 and 4 1 well Antagonists to v 3 or 4 1 effectively suppressed the interaction suggesting that the interaction is specific Using an integrin 1 mutant 1-3-1 that has a small fragment from the ligand binding site of 3 we showed that mCRP bound to the classical RGD-binding site in v 3 We studied the role of integrins in CRP signaling in monocytic U937 cells Integrins v 3 and 4 1 specifically mediated binding of mCRP to U937 cells mCRP induced AKT phosphorylation but not ERK1 2 phosphorylation in U937 cells Notably mCRP induced robust chemotaxis in U937 cells and antagonists to integrins v 3 and 4 1 and an inhibitor to phosphatidylinositide 3-kinase but not an MEK inhibitor effectively suppressed mCRP-induced chemotaxis in U937 cells These results suggest that the integrin and AKT phosphatidylinositide 3-kinase pathways play a role in pro-inflammatory action of mCRP in U937 cells In contrast pCRP is predicted to have a limited access to v 3 due to steric hindrance in the simulation Consistent with the prediction pCRP was much less effective in integrin binding chemotaxis or AKT phosphorylation These findings suggest that the ability of CRP isoforms to bind to the integrins is related to their pro-inflammatory action

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The binding of monomeric C-reactive protein (mCRP) to Integrins αvβ3 and α4β1 is related to its pro-inflammatory action....