1. Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor.
- Author
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Hariri BM, McMahon DB, Chen B, Freund JR, Mansfield CJ, Doghramji LJ, Adappa ND, Palmer JN, Kennedy DW, Reed DR, Jiang P, and Lee RJ
- Subjects
- A549 Cells, Humans, Immunity, Innate genetics, Mucin 5AC genetics, Mucin 5AC immunology, Nitric Oxide genetics, Nitric Oxide immunology, Nitric Oxide Synthase Type II genetics, Polymorphism, Genetic, Receptors, G-Protein-Coupled genetics, Anti-Inflammatory Agents pharmacology, Flavones pharmacology, Immunity, Innate drug effects, Nasal Mucosa immunology, Nitric Oxide Synthase Type II immunology, Receptors, G-Protein-Coupled immunology
- 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. TAS2R38 polymorphisms encode functional (PAV: p roline, a lanine, and v aline at positions 49, 262, and 296, respectively) or non-functional (AVI: a lanine, v aline, i soleucine 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., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2017
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