The binding of monomeric C-reactive protein (mCRP) to Integrins αvβ3 and α4β1 is related to its pro-inflammatory action.
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 αvβ3 predicted that mCRP binds to αvβ3 well. We found that mCRP actually bound to integrins αvβ3 and α4β1 well. Antagonists to αvβ3 or α4β1 effectively suppressed the interaction, suggesting that the interaction is specific. Using an integrin β1 mutant (β1-3-1) that has a small fragment from the ligand binding site of β3, we showed that mCRP bound to the classical RGD-binding site in αvβ3. We studied the role of integrins in CRP signaling in monocytic U937 cells. Integrins αvβ3 and α4β1 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 αvβ3 and α4β1 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 αvβ3 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.
Departments of Dermatology, and Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, California, United States of America.
Masaaki
M
Fujita
Departments of Dermatology, and Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, California, United States of America.
Yoko K
YK
Takada
Departments of Dermatology, and Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, California, United States of America.
Yoshihiro
Y
Izumiya
Departments of Dermatology, and Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, California, United States of America.
Yoshikazu
Y
Takada
D000818:Animals; D002097:C-Reactive Protein / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D003412:Cricetulus; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding; D020298:U937 Cells
D039041:Integrin alpha4beta1; D039302:Integrin alphaVbeta3; D002097:C-Reactive Protein