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A redox switch in C‐reactive protein modulates activation of endothelial cells
Author(s) -
Wang MingYu,
Ji ShangRong,
Bai CaiJuan,
Kebir iss El,
Li HaiYun,
Shi JingMing,
Zhu Wei,
Costantino Santiago,
Zhou HaiHong,
Potempa Lawrence A.,
Zhao Jing,
Filep János G.,
Wu Yi
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-182741
Subject(s) - chemistry , proinflammatory cytokine , microbiology and biotechnology , inflammation , thioredoxin , biochemistry , oxidative stress , biology , immunology
C‐reactive protein (CRP) has been implicated in the regulation of inflammation underlying coronary artery disease; however, little is known about the molecular mechanisms responsible for the expression of its pro‐ or anti‐inflammatory activities. Here, we have identified the intrasubunit disulfide bond as a conserved switch that controls the structure and functions of CRP. Conformational rearrangement in human pentameric CRP to monomeric CRP (mCRP) is the prerequisite for this switch to be activated by reducing agents, including thioredoxin. Immunohistochemical analysis revealed 36‐79% colocalization of thioredoxin and mCRP in human advanced coronary atherosclerotic lesions. Nonreduced mCRP was largely inert in activating human coronary artery endothelial cells (HCAECs), whereas reduced or cysteine‐mutated mCRP evoked marked release of IL‐8 and monocyte chemoattractant protein‐1 from HCAECs, with ~50% increase at a concentration of 1 μg/ml. Reduced mCRP was ~4 to 40‐fold more potent than mCRP in up‐regulating adhesion molecule expression, promoting U937 monocyte adhesion to HCAECs, and inducing cytokine release from rabbit arteries ex vivo and in mice. These actions were primarily due to unlocking the lipid raft interaction motif. Therefore, expression of proinflammatory properties of CRP on endothelial cells requires sequential conformational changes, i.e. , loss of pentameric symmetry followed by reduction of the intrasubunit disulfide bond.—Wang M‐Y., Ji, S‐R., Bai, C‐J., El Kebir, D., Li, H‐Y., Shi, J‐M., Zhu, W., Costantino, S., Zhou, H‐H., Potempa, L. A., Zhao, J., Filep, J. G., Wu, Y. A redox switch in C‐reactive protein modulates activation of endothelial cells. FASEB J. 25, 3186‐3196 (2011). www.fasebj.org