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European Journal of Nutrition

Erschienen in:

28.03.2016 | Original Contribution

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

verfasst von: Yvonne Hagenlocher, Katharina Feilhauer, Michael Schäffer, Stephan C. Bischoff, Axel Lorentz

Erschienen in: European Journal of Nutrition | Ausgabe 4/2017

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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.

Li S, Lo C-Y, Ho C-T (2001) Hydroxylated polymethoxyflavones and methylated flavonoids in sweet orange (Citrus sinensis) peel. J Agric Food Chem 54:4176–4185CrossRef

Boeing H, Bechthold A, Bub A, Ellinger S, Haller D, Kroke A, Leschik-Bonnet E, Müller MJ, Oberritter H, Schulze M, Stehle P, Watzl B (2012) Critical review: vegetables and fruit in the prevention of chronic diseases. Eur J Nutr 51:637–663CrossRef

Murakami A, Nakamura Y, Torikai K (2000) Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res 60:5059–5066

Suzuki R, Kohno H, Murakami A, Koshimizu K, Ohigashi H, Yano M, Takuda H, Nishino H, Tanaka T (2004) Citrus nobiletin inhibits azoxymethane-induced large bowel carcinogenesis in rats. BioFactors 21:111–114CrossRef

Tang MX, Ogawa K, Asamoto M, Chewonarin T, Suzuki S, Tanaka T, Shirai T (2011) Effects of nobiletin on PhIP-induced prostate and colon carcinogenesis in F344 rats. Nutr Cancer 63:227–233CrossRef

Dong Y, Cao A, Shi J, Yin P, Wang L, Ji G, Xie J, Wu D (2014) Tangeretin, a citrus polymethoxyflavonoid, induces apoptosis of human gastric cancer AGS cells through extrinsic and intrinsic signaling pathways. Oncol Rep 31:1788–1794

Lee YC, Cheng TH, Lee JS, Chen JH, Liao YC, Fong Y, Wu CH, Shih YW (2011) Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3 K/Akt and small GTPase signals in human gastric adenocarcinoma AGS cells. Mol Cell Biochem 347:103–115CrossRef

Miyata Y, Sato T, Yano M, Ito A (2004) Activation of protein kinase C βII/ε-c-Jun NH₂-terminal kinase pathway and inhibition of mitogen-activated protein/extracellular signal-regulated kinase 1/2 phosphorylation in antitumor invasive activity induced by the polymethoxyflavonoid nobiletin. Mol Cancer Therapeutics 3:839–847

Martínez Conesa C, Vicente Ortega V, Yánez Gascón MJ, Alcaraz Banos M, Canteras Jordana M, Benavente-García O, Castillo J (2005) Treatment of metastatic melanoma B16F10 by the flavonoids tangeretin, rutin, and diosmin. J Agric Food Chem 53:6791–6797CrossRef

10.

Lee Y-S, Cha B-Y, Saito K, Yamakawa H, Choi S-S, Yamaguchi K, Yonezawa T, Teruya T, Nagai K, Woo J-T (2010) Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. Biochem Pharmacol 79:1674–1683CrossRef

11.

Lee YS, Cha BY, Choi SS, Choi BK, Yonezawa T, Teruya T, Nagai K, Woo JT (2013) Nobiletin improves obesity and insulin resistance in high-fat diet-induced obese mice. J Nutr Biochem 24:156–162CrossRef

12.

Sundaram R, Shanthi P, Sachdanandam P (2014) Effect of tangeretin, a polymethoxylated flavone, on glucose metabolism in streptozotocin-induced diabetic rats. Phytomedicine 21:793–799CrossRef

13.

Nakajima A, Yamakuni T, Haraguchi M, Omae N, Song SY, Kato C, Nakagawasai O, Tadano T, Yokosuka A, Mimaki Y, Sashida Y, Ohizumi Y (2007) Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice. J Pharmacol Sci 105:122–126CrossRef

14.

Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D, Tetsu N, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y (2008) Nobiletin, a citrus flavonoid, improves memory impairment and Aβ pathology in a transgenic mouse model of Alzheimer’s disease. J Pharmacol Exp Therapeutics 326:739–744CrossRef

15.

Datla KP, Christidou M, Widmer WW, Rooprai HK, Dexter DT (2001) Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of parkinson’s disease. Neuroreport 12:3871–3875CrossRef

16.

Seki T, Kamiya T, Furukawa K, Azumi M, Ishizuka S, Takayama S, Nagase S, Arai H, Yamakuni T, Yaegashi N (2013) Nobiletin-rich citrus reticulate peels, a kampo medicine for Azheimer’s disease: a case series. Geriatr Gerontol Int 13:236–238CrossRef

17.

Wu Y-Q, Zhou C-H, Tao J, Li S-N (2006) Antagonistic effects of nobiletin, a polymethoxyflavonoid, on eosinophilic airway inflammation of asthmatic rats and relevant mechanisms. Life Sci 78:2689–2696CrossRef

18.

Cui Y, Wu J, Jung SC, Park DB, Maeng YH, Hong JY, Kim SJ, Lee SR, Kim SJ, Kim SJ, Eun SY (2010) Anti-neuroinflammatory activity of nobiletin on suppression of microglial activation. Biol Pharm Bull 33:1814–1821CrossRef

19.

Guo S, Qiu P, Xu G, Wu X, Dong P, Yang G, Zheng J, McClements DJ, Xiao H (2012) Synergistic anti-inflammatory effects of nobiletin and sulforaphane in lipopolysaccharide-stimulated RAW 264.7 cells. J Agric Food Chem 60:2157–2164CrossRef

20.

Imada K, Lin N, Liu C, Lu A, Chen W, Yano M, Sato T, Ito A (2008) Nobiletin, a citrus polymethoxy flavonoid, suppresses gene expression and production of aggrecanases-1 and -2 in collagen-induced arthritic mice. Biochem Biophys Res Commun 373:181–185CrossRef

21.

Tominari T, Hirata M, Matsumoto C, Inada M, Miyaura C (2012) Polymethoxy flavonoids, nobiletin and tangeretin, prevent lipopolysaccharide-induced inflammatory bone loss in an experimental model of periodontitis. J Pharmacol Sci 119:390–394CrossRef

22.

Xu JJ, Liu Z, Tang W, Wang GC, Chung HY, Liu QY, Zhuang L, Li MM, Li YL (2015) Tangeretin from Citrus reticulate inhibits respiratory syncytial virus replication and associated inflammation in vivo. J Agric Food Chem 63:95290–95297

23.

Choi S-Y, Hwang J-H, Ko H-C, Park J-G, Kim S-J (2007) Nobiletin from citrus peel inhibits the DNA-binding activity of NF-κB and ROS production in LPS-activated RAW 264.7 cells. J Ethnopharmacol 113:149–155CrossRef

24.

Lin N, Sato T, Takayama Y, Mimaki Y, Sashida Y, Yano M, Ito A (2003) Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem Pharmacol 65:2065–2071CrossRef

25.

Murakami A, Shigemori T, Ohigashi H (2005) Zingiberaceous and citrus constituents, 1′-acetoxychavicol acetate, zerumbone, auraptene, and nobiletin, suppress lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 murine macrophages through different modes of action. J Nutr 135:2987S–2992S

26.

Hirata Y, Masuda Y, Kakutani H, Higuchi T, Takada K, Ito A, Nakagawa Y, Ishii H (2008) Sp1 is an essential transcription factor for LPS-induced tissue factor expression in THP-1 monocytic cells, and nobiletin represses the expression through inhibition of NF-κB, AP-1 and Sp1 activation. Biochem Pharmacol 75:1504–1514CrossRef

27.

Choi S-Y, Ko H-C, Ko S-Y, Hwang J-H, Park J-G, Kang S-H, Han S-H, Yun S-H, Kim S-J (2007) Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol Pharm Bull 30:772–778CrossRef

28.

Onishi S, Nishi K, Yasunaga S, Muranaka A, Maeyama K, Kadato A, Sugahara T (2014) Nobiletin, a polymethoxy flavonoid, exerts anti-allergic effects by suppressing activation of phosphoinositide 3-kinase. J Funct Foods 6:6906–6914CrossRef

29.

Jang SE, Ryu KR, Park SH, Chung S, Teruya Y, Han MJ, Woo JT, Kim DH (2013) Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-κB, AP-1 and p38. Int Immunopharmacol 17:502–507CrossRef

30.

Bischoff SC (2009) Physiological and pathophysiological functions of intestinal mast cells. Semin Immunpathol 31:185–205CrossRef

31.

Bischoff SC (2007) Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data. Nat Rev Immunol 7:93–104CrossRef

32.

Kalesnikoff J, Galli SJ (2008) New developments in mast cell biology. Nat Immunol 9:1215–1223CrossRef

33.

Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911–920CrossRef

34.

Lorentz A, Sellge G, Bischoff SC (2015) Isolation and characterization of human intestinal mast cells. Methods Mol Biol 1220:163–177CrossRef

35.

Brenner SA, Zacheja S, Schäffer M, Feilhauer K, Bischoff SC, Lorentz A (2014) Soluble CD14 is essential for lipopolysaccharide-dependent activation of human intestinal mast cells from macroscopically normal as well as Crohn’s disease tissue. Immunology 143:174–183CrossRef

36.

Schwartz LB, Austen KF, Wasserman SI (1979) Immunological release of beta hexosaminidase and beta-glucuronidase from purified rat serosal mast cells. J Immunol 123:1445–1450

37.

Feuser K, Feilhauer K, Staib L, Bischoff SC, Lorentz A (2011) Akt cross-links IL-4 priming, stem cell factor signaling, and IgE-dependent activation in mature human mast cells. Mol Immunol 48:546–552CrossRef

38.

Lorentz A, Wilke M, Sellge G, Worthmann H, Klempnauer J, Manns MP et al (2005) IL-4 induced priming of human intestinal mast cells for enhanced survival and Th2 cytokine generation is reversible and associated with increased activity of ERK1/2 and c-FOS. J Immunol 174:6751–6756CrossRef

39.

Dudley DT, Pang L, Decker SJ, Bridges AJ, Satiel AR (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 92:7686–7689CrossRef

40.

Ihara H, Yamamoto H, Ida T, Tsutsuki H, Sakamoto T, Fujita T, Okada T, Kozaki S (2012) Inhibition of nitric oxide production and inducible nitric oxide synthase expression by a polymethoxyflavone from young fruits of Citrus unshui in rat primary astrocytes. Biosci Biotechnol Biochem 76:1843–1848CrossRef

41.

Shu Z, Yang B, Zhao H, Xu B, Jiao W, Wang Q, Wang Z, Kuang H (2014) Tangeretin exerts anti-neuroinflammatory effects via NF-κB modulation in lipopolysaccharide-stimulated microglial cells. Int Immunopharmacol 19:275–282CrossRef

42.

Aoki K, Yokosuka A, Mimaki Y, Fukunaga K, Yamakuni T (2013) Nobiletin induces inhibitions of Ras activity and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling to suppress cell proliferation in C6 rat glioma cells. Biol Pharm Bull 36:540–547CrossRef

43.

Miyata Y, Sato T, Imada K, Dobashi A, Yano M, Ito A (2008) A citrus polymethoxyflavonoid, nobiletin, is a novel MEK inhibitor that exhibits antitumor metastasis in human fibrosarcoma HT-1080 cells. Biochem Biophys Res Commun 366:168–173CrossRef

44.

Van Slambrouck S, Parmar VS, Sharma SK, De Bondt B, Foré F, Coopman P, Vanhoecke BW, Boterberg T, Depypere HT, Leclercq G, Bracke ME (2005) Tangeretin inhibits extracellular-signal-regulated kinase (ERK) phosphorylation. FEBS Lett 579:1665–1669CrossRef

Titel: Citrus peel polymethoxyflavones nobiletin and tangeretin suppress LPS- and IgE-mediated activation of human intestinal mast cells
verfasst von: Yvonne Hagenlocher
Katharina Feilhauer
Michael Schäffer
Stephan C. Bischoff
Axel Lorentz
Publikationsdatum: 28.03.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nutrition / Ausgabe 4/2017
Print ISSN: 1436-6207
Elektronische ISSN: 1436-6215
DOI: https://doi.org/10.1007/s00394-016-1207-z

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

Abstract

Purpose

Methods

Results

Conclusions

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