title: Mapracorat, a selective glucocorticoid receptor agonist, upregulates RelB, an anti-inflammatory nuclear factor-kappaB protein, in human ocular cells.
abstract: Selective glucocorticoid receptor agonists (SEGRAs) are a new class of compounds under clinical evaluation for treatment of ocular inflammation. Widely prescribed therapeutics, such as glucocorticoids, are effective at reducing ocular inflammation, but their long term use predisposes to undesirable side effects. The purpose of this study was to investigate a novel SEGRA, mapracorat (BOL-303242-X), and the differences in mapracorat's mechanism of action compared with traditional steroids (i.e. dexamethasone). Keratocytes from three different humans were cultured and treated with mapracorat or dexamethasone, with and without a strong provoking agent, interleukin (IL)-1β. The effects of mapracorat compared to dexamethasone were determined by measuring protein levels (Western blotting) and DNA binding (ELISA) for two nuclear factor-kappaB (NF-κB) family members, RelA and RelB. Cytokine production (i.e. IL-6, IL-8, prostaglandin E2 (PGE2)) was characterized by immunoassay. Our findings reveal mechanistic differences between mapracorat and traditional steroid therapies. Mapracorat showed partial attenuation of the classical NF-κB pathway, consistent with traditional steroids. However, mapracorat uniquely potentiated a novel anti-inflammatory mechanism through rapid upregulation of RelB, an anti-inflammatory member of the NF-κB alternative pathway. Mapracorat potently inhibits ocular inflammation in vitro and is a promising new treatment for ocular inflammatory disease. Mapracorat acts, in part, by a novel mechanism via upregulation of RelB in the NF-κB alternative pathway.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Spinelli
authors.affiliation: Department of Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Xi
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: McMillan
authors.affiliation: Environmental Medicine, Lung and Biology Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Collynn F
authors.initials: CF
authors.lastname: Woeller
authors.affiliation: Global Pharmaceutical R&D, Bausch & Lomb, Inc., Rochester, NY, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Richardson
authors.affiliation: Global Pharmaceutical R&D, Bausch & Lomb, Inc., Rochester, NY, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Cavet
authors.affiliation: Global Pharmaceutical R&D, Bausch & Lomb, Inc., Rochester, NY, USA.
authors.forename: Jin-Zhong
authors.initials: JZ
authors.lastname: Zhang
authors.affiliation: Flaum Eye Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Feldon
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Department of Ophthalmology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Environmental Medicine, Lung and Biology Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Flaum Eye Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address: richard_phipps@urmc.rochester.edu.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D060527:Corneal Keratocytes / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D000439:Pentanols / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D051996:Transcription Factor RelA / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D001572:Benzofurans; D016207:Cytokines; D005938:Glucocorticoids; D016328:NF-kappa B; D000439:Pentanols; D011804:Quinolines; C546413:R-1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(((2-methyl-5-quinolyl)amino)methyl)pentan-2-ol; D011965:Receptors, Glucocorticoid; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D003907:Dexamethasone
keywords: NF-κB; RelB; cytokine; glucocorticoid; inflammation; mapracorat; ocular; steroid