title: Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor.
abstract: Chronic rhinosinusitis has a significant impact on patient quality of life, creates billions of dollars of annual healthcare costs, and accounts for ∼20% of adult antibiotic prescriptions in the United States. Because of the rise of resistant microorganisms, there is a critical need to better understand how to stimulate and/or enhance innate immune responses as a therapeutic modality to treat respiratory infections. We recently identified bitter taste receptors (taste family type 2 receptors, or T2Rs) as important regulators of sinonasal immune responses and potentially important therapeutic targets. Here, we examined the immunomodulatory potential of flavones, a class of flavonoids previously demonstrated to have antibacterial and anti-inflammatory effects. Some flavones are also T2R agonists. We found that several flavones inhibit Muc5AC and inducible NOS up-regulation as well as cytokine release in primary and cultured airway cells in response to several inflammatory stimuli. This occurs at least partly through inhibition of protein kinase C and receptor tyrosine kinase activity. We also demonstrate that sinonasal ciliated epithelial cells express T2R14, which closely co-localizes (<7 nm) with the T2R38 isoform. Heterologously expressed T2R14 responds to multiple flavones. These flavones also activate T2R14-driven calcium signals in primary cells that activate nitric oxide production to increase ciliary beating and mucociliary clearance.TAS2R38polymorphisms encode functional (PAV:proline,alanine, andvaline at positions 49, 262, and 296, respectively) or non-functional (AVI:alanine,valine,isoleucine at positions 49, 262, and 296, respectively) T2R38. Our data demonstrate that T2R14 in sinonasal cilia is a potential therapeutic target for upper respiratory infections and that flavones may have clinical potential as topical therapeutics, particularly in T2R38 AVI/AVI individuals.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Hariri
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery.
authors.forename: Derek B
authors.initials: DB
authors.lastname: McMahon
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery.
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery.
authors.forename: Jenna R
authors.initials: JR
authors.lastname: Freund
authors.affiliation: Monell Chemical Senses Center, Philadelphia, Pennsylvania 19104.
authors.forename: Corrine J
authors.initials: CJ
authors.lastname: Mansfield
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery.
authors.forename: Laurel J
authors.initials: LJ
authors.lastname: Doghramji
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery.
authors.forename: Nithin D
authors.initials: ND
authors.lastname: Adappa
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery.
authors.forename: James N
authors.initials: JN
authors.lastname: Palmer
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery.
authors.forename: David W
authors.initials: DW
authors.lastname: Kennedy
authors.affiliation: Monell Chemical Senses Center, Philadelphia, Pennsylvania 19104.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Reed
authors.affiliation: Monell Chemical Senses Center, Philadelphia, Pennsylvania 19104.
authors.forename: Peihua
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia. Electronic address: rjl@mail.med.upenn.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
mesh_terms: D000072283:A549 Cells; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics; D055271:Mucin 5AC / Q000235:genetics / Q000276:immunology; D009297:Nasal Mucosa / Q000276:immunology*; D009569:Nitric Oxide / Q000235:genetics / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology*; D000098706:Taste Receptors, Type 2
chemical_list: D000893:Anti-Inflammatory Agents; D047309:Flavones; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
keywords: airway surface liquid; antimicrobial peptide (AMP); bitter taste receptor; chronic rhinosinusitis; flavonoid; innate immunity; mucociliary clearance; nitric oxide; polyphenol; protein kinase C (PKC)