title: Vitamin E is a MIF Inhibitor.
abstract: Macrophage migration inhibitory factor (MIF) is known to contribute to the pathogenesis of inflammatory hyperalgesia and neuropathic pain. Prior studies have shown that Vitamin E treatment is associated with attenuated hyperalgesia and reduced neuropathic pain in rodents. Given these observations, we investigated the possibility that Vitamin E is a MIF inhibitor. Dopachrome tautomerase assays revealed that Vitamin E inhibits the enzymatic activity of purified human recombinant MIF (rhMIF) in a dose-dependent manner (45%, 74%, 92% and 100% inhibition at 3, 10, 30 and 100μM, respectively). Cell-free ELISA based assays showed that Vitamin E binds onto rhMIF thereby blocking its recognition (48% inhibition at 100μM). Circular dichroism studies indicated the Vitamin E has a strong affinity to bind to rhMIF (binding constant 19.52±1.4μM). In silico studies demonstrated that Vitamin E docks well in the active site of MIF with the long aliphatic chain of Vitamin E exhibiting strong van der Waals interactions with MIF. Most importantly, human cell-based assays revealed that Vitamin E significantly inhibits rhMIF-induced production of pro-inflammatory cytokines in a dose-dependent manner (77%, 80%, and 96% inhibition of IL-6 production, respectively, at 10, 30 and 100μM). Taken together, these results demonstrate that Vitamin E inhibits not only the enzymatic activity of MIF but more importantly the biological function of MIF. Our findings suggest that Vitamin E may be attenuating hyperalgesia and reducing neuropathic pain at least in part by inhibiting MIF activity.
authors.affiliation: The Department of High Throughput Screening, NCE-Unit of Piramal Healthcare Limited, Mumbai, Maharashtra, India.
authors.forename: Bindu
authors.initials: B
authors.lastname: Hegde
authors.forename: Prashant
authors.initials: P
authors.lastname: Vadnal
authors.forename: Jingal
authors.initials: J
authors.lastname: Sanghavi
authors.forename: Vaidehi
authors.initials: V
authors.lastname: Korde
authors.forename: Asha A
authors.initials: AA
authors.lastname: Kulkarni-Almeida
authors.forename: Nilesh M
authors.initials: NM
authors.lastname: Dagia
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation; D014810:Vitamin E / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D008263:Macrophage Migration-Inhibitory Factors; D014810:Vitamin E; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human