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Citrus peel polymethoxyflavones nobiletin and tangeretin suppress LPS- and IgE-mediated activation of human intestinal mast cells

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Abstract

Purpose

Allergic diseases with mast cells (MC) as main effector cells show an increased prevalence. MC also play an essential role in other inflammatory conditions. Therapeutical use of anti-inflammatory nutraceuticals directly targeting MC activation could be of interest for afflicted patients. Nobiletin and tangeretin are citrus peel polymethoxyflavones, a group of citrus flavonoids, possessing anticancer, antimetastatic, and anti-inflammatory activities. Here, we analyzed the effects of nobiletin/tangeretin on LPS- and IgE-mediated stimulation of human intestinal mast cells (hiMC).

Methods

MC isolated from human intestinal tissue were treated with different concentrations of nobiletin or tangeretin prior to stimulation via LPS/sCD14 or IgE-dependently. Degranulation, pro-inflammatory cytokine expression and phosphorylation of ERK1/2 were examined.

Results

Expression of CXCL8, CCL3, CCL4 and IL-1β in response to LPS-mediated stimulation was inhibited by nobiletin/tangeretin. hiMC activated IgE-dependently showed a reduced release of β-hexosaminidase and cysteinyl LTC4 in response to nobiletin, but not in response to tangeretin. Expression of CXCL8, CCL2, CCL3, CCL4 and TNF in IgE-dependently activated hiMC was decreased in a dose-dependent manner following treatment with nobiletin/tangeretin. IL-1β expression was only reduced by tangeretin. Compared to treatment with NF-κB inhibitor BMS345541 or MEK-inhibitor PD98059, nobiletin and tangeretin showed similar effects on mediator production. Phosphorylation of ERK1/2 upon IgE-mediated antigen stimulation was significantly suppressed by nobiletin and tangeretin.

Conclusions

Nobiletin and, to a lesser extent, tangeretin could be considered as anti-inflammatory nutraceuticals by reducing release and production of proinflammatory mediators in MC.

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Acknowledgments

The authors thank Bernhard Watzl for helpful discussions and providing the citrus flavonoids, and thank Yvonne Soltow for excellent technical assistance.

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Authors and Affiliations

  1. Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70593, Stuttgart, Germany

    Yvonne Hagenlocher, Stephan C. Bischoff & Axel Lorentz

  2. Clinic for Visceral Surgery, Katharinenhospital, Kriegsbergstraße 60, 70174, Stuttgart, Germany

    Katharina Feilhauer

  3. Department of General, Visceral, and Thorax Surgery, Marienhospital, Böheimstraße 37, 70199, Stuttgart, Germany

    Michael Schäffer

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  1. Yvonne Hagenlocher
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  2. Katharina Feilhauer
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  3. Michael Schäffer
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  4. Stephan C. Bischoff
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  5. Axel Lorentz
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Correspondence to Axel Lorentz.

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The authors declare that they have no conflicts of interest.

Ethical standard

Surgery tissue specimen from patients undergoing bowel resection served for isolation of mature human MC. This study has been approved by the local ethics committee and has therefore been performed in accordance with the ethical standards. All persons gave their informed consent prior to their inclusion in the study.

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Hagenlocher, Y., Feilhauer, K., Schäffer, M. et al. Citrus peel polymethoxyflavones nobiletin and tangeretin suppress LPS- and IgE-mediated activation of human intestinal mast cells. Eur J Nutr 56, 1609–1620 (2017). https://doi.org/10.1007/s00394-016-1207-z

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  • DOI: https://doi.org/10.1007/s00394-016-1207-z

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