The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression

Scientific Reports

Volumn 5, Issue , 2015, Pages

  Bijsmans, Ingrid T G W ^a   Guercini, Chiara ^b   Ramos Pittol, José M ^a   Omta, Wienand ^a   Milona, Alexandra ^a   Lelieveld, Daphne ^a   Egan, David A ^a   Pellicciari, Roberto ^b   Gioiello, Antimo ^c   Van Mil, Saskia W C ^a  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^b TES Pharma Loc Taverne   (Italy)

^c UNIVERSITY OF PERUGIA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFLAMMATORY AGENT; CELL RECEPTOR; FARNESOID X-ACTIVATED RECEPTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LIGAND; MOMETASONE FUROATE; PROTEIN BINDING; TRANSCRIPTION FACTOR RELA; TUMOR NECROSIS FACTOR;

ANIMAL; CHEMISTRY; CONFORMATION; DRUG EFFECTS; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENETICS; HEP-G2 CELL LINE; HUMAN; INFLAMMATION; METABOLISM; MOLECULAR DOCKING; MOLECULAR MODEL; MOUSE; PROMOTER REGION; REPORTER GENE;

ANIMALS; ANTI-INFLAMMATORY AGENTS; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENES, REPORTER; HEP G2 CELLS; HUMANS; INFLAMMATION; LIGANDS; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR DOCKING SIMULATION; MOMETASONE FUROATE; NF-KAPPA B; PROMOTER REGIONS, GENETIC; PROTEIN BINDING; RECEPTORS, CYTOPLASMIC AND NUCLEAR; TRANSCRIPTION FACTOR RELA; TUMOR NECROSIS FACTOR-ALPHA;

EID: 84941710332     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep14086     Document Type: Article

References (31)

1. Burris, T. P. et al. Nuclear receptors and their selective pharmacologic modulators. Pharmacol Rev 65, 710-778 (2013).
2. Hollman, D. A., Milona, A., van Erpecum, K. J. & van Mil, S. W. Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms. Biochim Biophys Acta 1821, 1443-1452 (2012).
3. Glass, C. K. & Saijo, K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol 10, 365-376 (2010).
4. Schacke, H., Docke, W. D. & Asadullah, K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 96, 23-43 (2002).
5. De Bosscher, K., Haegeman, G. & Elewaut, D. Targeting inflammation using selective glucocorticoid receptor modulators. Curr Opin Pharmacol 10, 497-504 (2010).
6. Lefebvre, P., Cariou, B., Lien, F., Kuipers, F. & Staels, B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89, 147-191 (2009).
7. Matsukuma, K. E. et al. Coordinated control of bile acids and lipogenesis through FXR-dependent regulation of fatty acid synthase. J Lipid Res 47, 2754-2761 (2006).
8. Chong, H. K. et al. Genome-wide interrogation of hepatic FXR reveals an asymmetric IR-1 motif and synergy with LRH-1. Nucleic Acids Res 38, 6007-6017 (2010).
9. Gadaleta, R. M. et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60, 463-472 (2011).
10. Vavassori, P., Mencarelli, A., Renga, B., Distrutti, E. & Fiorucci, S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol 183, 6251-6261 (2009).
11. Wang, Y. D. et al. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48, 1632-1643 (2008).
12. Rouleau, N., Turcotte, S., Mondou, M. H., Roby, P. & Bosse, R. Development of a versatile platform for nuclear receptor screening using AlphaScreen. J Biomol Screen 8, 191-197 (2003).
13. Glickman, J. F. et al. A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors. J Biomol Screen 7, 3-10 (2002).
14. Kim, D. H. et al. A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. EMBO J 34, 184-199 (2015).
15. Saijo, K. et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137, 47-59 (2009).
16. Hsu, C. W. et al. Quantitative High-Throughput Profiling of Environmental Chemicals and Drugs that Modulate Farnesoid X Receptor. Sci Rep 4, 6437 (2014).
17. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262-265 (2009).
18. Berman, H. M. et al. The Protein Data Bank. Nucleic Acids Res 28, 235-242 (2000).
19. Pellicciari, R. et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 45, 3569-3572 (2002).
20. Mi, L. Z. et al. Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol Cell 11, 1093-1100 (2003).
21. He, Y. et al. Structures and mechanism for the design of highly potent glucocorticoids. Cell Res 24, 713-726 (2014).
22. Madauss, K. P. et al. Progesterone receptor ligand binding pocket flexibility: crystal structures of the norethindrone and mometasone furoate complexes. J Med Chem 47, 3381-3387 (2004).
23. Gadaleta, R. M. et al. Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NFkappaB signaling in the intestine. Biochim Biophys Acta 1812, 851-858 (2011).
24. www.clinicaltrial.gov A service of the U.S. National Institutes of Health. Date of access 09/01/2015. ClinicalTrial.gov Identifier NCT01999101 (NAFLD), NCT01265498 (NASH), NCT02308111 (PBC), NCT02177136 (PSC).
25. Gioiello, A. et al. Bile acid derivatives as ligands of the farnesoid x receptor: molecular determinants for bile acid binding and receptor modulation. Curr Top Med Chem 14, 2159-2174 (2014).
26. Austin, R. J. et al. Mometasone furoate is a less specific glucocorticoid than fluticasone propionate. Eur Respir J 20, 1386-1392 (2002).
27. King, E. M. et al. Glucocorticoid repression of inflammatory gene expression shows differential responsiveness by transactivationand transrepression-dependent mechanisms. PLoS One 8, e53936 (2013).
28. Bourke, J., Coulson, I., English, J., British Association of Dermatologists Therapy, G. & Audit, S. Guidelines for the management of contact dermatitis: an update. Br J Dermatol 160, 946-954 (2009).
29. Campeau, E. et al. A versatile viral system for expression and depletion of proteins in mammalian cells. PLoS One 4, e6529 (2009).
30. Saccani, S., Pantano, S. & Natoli, G. p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol 3, 69-75 (2002).
31. Nowak, D. E., Tian, B. & Brasier, A. R. Two-step cross-linking method for identification of NF-kappaB gene network by chromatin immunoprecipitation. Biotechniques 39, 715-725 (2005).