title: Potent inhibition of macrophage migration inhibitory factor (MIF) by myeloperoxidase-dependent oxidation of epicatechins.
abstract: 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.
authors.affiliation: *Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Nina
authors.initials: N
authors.lastname: Dickerhof
authors.affiliation: *Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Magon
authors.affiliation: †School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors.forename: Joel D A
authors.initials: JD
authors.lastname: Tyndall
authors.affiliation: *Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kettle
authors.affiliation: *Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Hampton
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D002392:Catechin / Q000737:chemistry*; D003198:Computer Simulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D007536:Isomerism; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010504:Periodic Acid / Q000737:chemistry; D009195:Peroxidase / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D010504:Periodic Acid; D002392:Catechin; C009288:metaperiodate; D006861:Hydrogen Peroxide; D009195:Peroxidase