MIF (macrophage migration inhibitory factor) plays a central role in the promotion and maintenance of the inflammatory response. It is implicated in a number of inflammatory diseases including sepsis, arthritis and colitis, and in diseases with an inflammatory component, such as atherosclerosis, diabetes and cancer. MIF has an unusual N-terminal proline with catalytic activity, and targeting of this residue by small-molecule inhibitors has been shown to interfere with the biological activity of MIF. The objective of the present study was to determine if MIF was susceptible to modification by epicatechins, a group of dietary flavonoids with known anti-inflammatory properties. Epicatechins are substrates for peroxidases including neutrophil-derived MPO (myeloperoxidase). In the present study we show that oxidation of the catechol moiety of epicatechins to an ο-quinone by MPO generates potent MIF inhibitors. Near complete inhibition of MIF by the MPO/H2O2/epicatechin system was achieved at equimolar concentrations of epicatechin and MIF, even in the presence of other MPO substrates. We have characterized the modification introduced by oxidized (−)-epicatechin on MIF by LC-MS (liquid chromatography MS) and found it to occur at the N-terminal proline. We propose that MIF inhibition by oxidized epicatechins contributes to the anti-inflammatory activity of these compounds.
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September 2014
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Research Article|
August 07 2014
Potent inhibition of macrophage migration inhibitory factor (MIF) by myeloperoxidase-dependent oxidation of epicatechins
Nina Dickerhof;
Nina Dickerhof
1
*Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand
1Correspondence may be addressed to either of these authors (email nina.dickerhof@otago.ac.nz or mark.hampton@otago.ac.nz).
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Nicholas J. Magon;
Nicholas J. Magon
*Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand
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Joel D. A. Tyndall;
Joel D. A. Tyndall
†School of Pharmacy, University of Otago, Dunedin, New Zealand
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Anthony J. Kettle;
Anthony J. Kettle
*Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand
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Mark B. Hampton
Mark B. Hampton
1
*Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand
1Correspondence may be addressed to either of these authors (email nina.dickerhof@otago.ac.nz or mark.hampton@otago.ac.nz).
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Publisher: Portland Press Ltd
Received:
May 14 2014
Accepted:
June 11 2014
Accepted Manuscript online:
June 11 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 462 (2): 303–314.
Article history
Received:
May 14 2014
Accepted:
June 11 2014
Accepted Manuscript online:
June 11 2014
Citation
Nina Dickerhof, Nicholas J. Magon, Joel D. A. Tyndall, Anthony J. Kettle, Mark B. Hampton; Potent inhibition of macrophage migration inhibitory factor (MIF) by myeloperoxidase-dependent oxidation of epicatechins. Biochem J 1 September 2014; 462 (2): 303–314. doi: https://doi.org/10.1042/BJ20140612
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