title: The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression.
abstract: The Farnesoid X receptor (FXR) regulates bile salt, glucose and cholesterol homeostasis by binding to DNA response elements, thereby activating gene expression (direct transactivation). FXR also inhibits the immune response via tethering to NF-κB (tethering transrepression). FXR activation therefore has therapeutic potential for liver and intestinal inflammatory diseases. We aim to identify and develop gene-selective FXR modulators, which repress inflammation, but do not interfere with its metabolic capacity. In a high-throughput reporter-based screen, mometasone furoate (MF) was identified as a compound that reduced NF-κB reporter activity in an FXR-dependent manner. MF reduced mRNA expression of pro-inflammatory cytokines, and induction of direct FXR target genes in HepG2-GFP-FXR cells and intestinal organoids was minor. Computational studies disclosed three putative binding modes of the compound within the ligand binding domain of the receptor. Interestingly, mutation of W469A residue within the FXR ligand binding domain abrogated the decrease in NF-κB activity. Finally, we show that MF-bound FXR inhibits NF-κB subunit p65 recruitment to the DNA of pro-inflammatory genes CXCL2 and IL8. Although MF is not suitable as selective anti-inflammatory FXR ligand due to nanomolar affinity for the glucocorticoid receptor, we show that separation between metabolic and anti-inflammatory functions of FXR can be achieved.
authors.affiliation: Center for Molecular Medicine, UMC Utrecht, Utrecht, the Netherlands.
authors.forename: Ingrid T G W
authors.initials: IT
authors.lastname: Bijsmans
authors.affiliation: TES Pharma, Loc. Taverne, Corciano (Perugia), Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Guercini
authors.affiliation: Center for Molecular Medicine, UMC Utrecht, Utrecht, the Netherlands.
authors.forename: José M
authors.initials: JM
authors.lastname: Ramos Pittol
authors.affiliation: Cell Screening Core, Department of Cell Biology, UMC Utrecht, Utrecht, the Netherlands.
authors.forename: Wienand
authors.initials: W
authors.lastname: Omta
authors.affiliation: Center for Molecular Medicine, UMC Utrecht, Utrecht, the Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Milona
authors.affiliation: Cell Screening Core, Department of Cell Biology, UMC Utrecht, Utrecht, the Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: Lelieveld
authors.affiliation: Cell Screening Core, Department of Cell Biology, UMC Utrecht, Utrecht, the Netherlands.
authors.forename: David A
authors.initials: DA
authors.lastname: Egan
authors.affiliation: TES Pharma, Loc. Taverne, Corciano (Perugia), Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.affiliation: Center for Molecular Medicine, UMC Utrecht, Utrecht, the Netherlands.
authors.forename: Saskia W C
authors.initials: SW
authors.lastname: van Mil
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D000068656:Mometasone Furoate / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000893:Anti-Inflammatory Agents; D008024:Ligands; D000068656:Mometasone Furoate; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099150:Receptor, Farnesoid X-Activated