Activation of human bitter taste receptors by polymethoxylated flavonoids

Kuroda, Yuki; Ikeda, Riko; Yamazaki, Toyomi; Ito, Keisuke; Uda, Kazunari; Wakabayashi, Keiji; Watanabe, Tatsuo

doi:10.1080/09168451.2016.1184558

Cited by 24 publications

(16 citation statements)

References 25 publications

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“…The above data suggest that flavones modify sinonasal epithelial inflammation-induced up-regulation of Muc5AC, iNOS, and cytokines. As mentioned above, apigenin and chrysin may also activate T2R14 and T2R39 (61), whereas tangeritin may activate T2R14 and T2R46 but not T2R39 (99). We hypothesized that flavones may activate one or more of these T2Rs located in the upper respiratory epithelium (22,25).…”

Section: Flavones Activate T2r14 Expressed In Sinonasal Epithelial Cementioning

confidence: 87%

Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor

Hariri¹,

McMahon²,

Chen³

et al. 2017

Journal of Biological Chemistry

100

176

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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. polymorphisms encode functional (PAV:roline, lanine, andaline at positions 49, 262, and 296, respectively) or non-functional (AVI: lanine,aline, 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.

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Section: Flavones Activate T2r14 Expressed In Sinonasal Epithelial Cementioning

confidence: 87%

Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor

Hariri¹,

McMahon²,

Chen³

et al. 2017

Journal of Biological Chemistry

100

176

View full text Add to dashboard Cite

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“…In MFs encountering bitter bacterial agonists at sites of infection, activated T2Rs may "rev up" acute phagocytic activity while likely simultaneous toll-like receptor (TLR) stimulation up-regulates expression of iNOS and antimicrobial proteins such as lysozyme to further combat infection. Of note, T2Rs also respond to a variety of natural plant compounds associated with complementary medicines, including flavonoids [8,[47][48][49], as well as common clinical drugs [50,51]. Activation of extraoral T2Rs in MFs may underlie some effects of homeopathic plant-based treatments or off-target drug effects.…”

Section: Discussionmentioning

confidence: 99%

“…3A-B; next page). Responses were blocked by pertussis toxin (PTX; Fig 3C), which ADP-ribosylates and inactivates Gαs that can couple to T2Rs (G i (47) and/or G gustducin (48)(49)(50) ). Responses to bacterial T2R14 agonist HHQ were blocked by T2R14 antagonist 4-fluoro-6methoxy-flavanone (15,51) (Fig.…”

Section: Data Analysis and Statisticsmentioning

confidence: 99%

Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling

Gopallawa

Freund

Lee

2019

Preprint

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Bitter taste receptors (T2Rs) are GPCRs involved in detection of bitter compounds by type 2 taste cells of the tongue, but are also expressed in other tissues throughout the body, including the airways, gastrointestinal tract, and brain. These T2Rs can be activated by several bacterial products and regulate innate immune responses in several cell types. Expression of T2Rs has been demonstrated in immune cells like neutrophils; however, the molecular details of their signaling are unknown. We examined mechanisms of T2R signaling in primary human monocyte-derived unprimed (M0) macrophages (MFs) using live cell imaging techniques. Known bitter compounds and bacterial T2R agonists activated low-level calcium signals through a pertussis toxin (PTX)-sensitive, phospholipase C-dependent, and inositol trisphosphate receptor-dependent calcium release pathway. These calcium signals activated low-level nitric oxide (NO) production via endothelial and neuronal NO synthase (NOS) isoforms. NO production increased cellular cGMP and enhanced acute phagocytosis ~3-fold over 30-60 min via protein kinase G. In parallel with calcium elevation, T2R activation lowered cAMP, also through a PTX-sensitive pathway. The cAMP decrease also contributed to enhanced phagocytosis. Moreover, a co-culture model with airway epithelial cells demonstrated that NO produced by epithelial cells can also acutely enhance MF phagocytosis. Together, these data define MF T2R signal transduction and support an immune recognition role for T2Rs in MF cell physiology.

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“…Prior studies of sinonasal immunity have demonstrated a T2R‐mediated mechanism for increases in CBF and other local immune defenses such as the release of NO and secretion of antimicrobial compounds . It is known that T2R activation by secreted bacterial products as well as other biologically active compounds results in NO production, which is not only directly bactericidal but also increases CBF. To determine whether the topical application of bacterial lysate may work by a similar mechanism of action, ALIs were pretreated with either a NOS inhibitor or inhibitors of bitter taste‐receptor signal transduction.…”

Section: Discussionmentioning

confidence: 99%

“…Recent research has provided support for the role of taste receptors in the sinonasal epithelium to sense their environment and initiate local immune defenses including mucociliary clearance and antimicrobial product release . These taste receptors are known to be activated by secreted bacterial products, and other compounds with biological activity are continuously being discovered . Given this emerging role of the sinonasal epithelium in the regulation of upper airway immunity, the nasal delivery of topical agents that augment the natural host response is an attractive therapeutic option in the treatment of rhinosinusitis and other local disease.…”

mentioning

confidence: 99%

Broncho‐Vaxom® (OM‐85 BV) soluble components stimulate sinonasal innate immunity

Triantafillou

Workman

Patel

et al. 2019

Int Forum Allergy Rhinol

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Background: Broncho-Vaxom R (OM-85 BV) is an extract of infectious respiratory bacteria that is used as an immunostimulant outside of the United States for the prevention and treatment of bronchitis and rhinosinusitis. Prior studies have shown that use of OM-85 BV is associated with reduction in frequency of respiratory infection and decreased duration of antibiotic usage. However, the effects of OM-85 BV on respiratory mucosal innate immunity are unknown. Methods:Human sinonasal epithelial cells were grown at an air-liquid interface (ALI). Ciliary beat frequency (CBF) and nitric oxide (NO) production in response to stimulation with OM-85 BV was measured in vitro. Pharmacologic inhibitors of bi er taste receptor (T2R) signaling were used to determine if this pathway was taste-receptor-mediated. Results:Apical application of OM-85 BV resulted in an NOmediated increase in CBF (p < 0.05) and increased NO production (p < 0.0001) when compared to saline-stimulated control cultures. ALI pretreatment with taste receptor pathway inhibitors blocked OM-85 BV-induced increases in NO.Conclusion: OM-85 BV has ciliostimulatory and immunogenic properties that may be partially responsible for its observed efficacy as a respiratory therapeutic. These responses were NO-dependent and consistent with T2R activation. Further work is necessary to elucidate specific component-receptor signaling relationships. C 2019 ARS-AAOA, LLC.

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Activation of human bitter taste receptors by polymethoxylated flavonoids

Cited by 24 publications

References 25 publications

Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor

Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor

Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling

Broncho‐Vaxom® (OM‐85 BV) soluble components stimulate sinonasal innate immunity

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