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European Journal of Nutrition

, Volume 58, Issue 4, pp 1391–1401 | Cite as

Nobiletin acts anti-inflammatory on murine IL-10−/− colitis and human intestinal fibroblasts

  • Yvonne Hagenlocher
  • Sonja Gommeringer
  • Anna Held
  • Katharina Feilhauer
  • Jörg Köninger
  • Stephan C. Bischoff
  • Axel LorentzEmail author
Original Contribution

Abstract

Purpose

Inflammatory bowel disease (IBD) shows increasing prevalence over the last years. We propose that anti-inflammatory plant substances could be used as additional or alternative agents with good compliance in prevention and/or therapy of IBD and its complication intestinal fibrosis. We could recently show that the citrus flavonoid nobiletin acts anti-inflammatory on activation of intestinal mast cells. Here, we analysed the effects of nobiletin on inflammation and fibrosis in IL-10−/− colitis.

Methods

IL-10−/− and wild-type (WT) mice were orally treated with/without vehicle or nobiletin. Clinical symptoms of colitis and disease activity index (DAI) were assessed, and colon tissue was analysed for tissue damage, cellular infiltration, bowel wall thickness, mast cell number and degranulation, as well as collagen deposition as marker for fibrosis. Human intestinal fibroblasts (hiFB) were treated with nobiletin and the expression of collagen and pro-inflammatory cytokines was measured.

Results

Nobiletin treatment of IL-10−/− mice resulted in a reduction of clinical colitis symptoms and a longer survival time. In addition, histological scores of colitis were reduced compared to control groups. Mast cell number and degranulation was lower in nobiletin treated IL-10−/− mice, and correlated positively with DAI. As well, fibrotic marker of collagen deposition was reduced by nobiletin. In hiFB, the expression of collagen as well as of pro-inflammatory cytokines IL-6, TNF and CCL2 was down-regulated by nobiletin treatment.

Conclusions

Nobiletin decreases inflammatory symptoms and markers in murine colitis as well as fibrotic collagen deposition and expression. Thus, nobiletin could be a potential new agent in therapy of chronic colitis.

Keywords

Nobiletin Colitis Fibroblasts Fibrosis Inflammation Nutraceuticals 

Notes

Acknowledgements

The authors thank Yvonne Soltow for excellent technical assistance.

Compliance with ethical standards

Ethical standards

Surgery tissue specimen from patients undergoing bowel resection served for isolation of human fiboblasts. This study has been approved by the local ethics committee and has therefore been performed in accordance with the ethical standards.

Informed consent

All persons gave their informed consent prior to their inclusion in the study.

Conflict of interest

All authors declare no conflicts of interest.

References

  1. 1.
    M’Koma AE (2013) Inflammatory bowel disease: an expanding global health problem. Clin Med Insights Gastroenterol 6:33–47Google Scholar
  2. 2.
    Preiß J, Bokemeyer B, Buhr H, Dignaß A, Häuser W, Hartmann F et al (2014) Aktualisierte S3-Leitlinie—“Diagnostik und Therapie updated german clinical practice guideline on” Diagnosis and treatment of Crohn’s disease” 2014. Z Gastroenterol 52:1431–1484CrossRefGoogle Scholar
  3. 3.
    Baumgart DC, Baumgart DC, Carding SR, Carding SR (2007) Series gastroenterology 1 Inflammatory bowel disease: cause and immunobiology. Lancet 369:1627–1640CrossRefGoogle Scholar
  4. 4.
    Luchini AC, Rodrigues-Orsi P, Cestari SH, Seito LN, Witaicenis A, Pellizzon CH, Di Stasi LC (2008) Intestinal anti-inflammatory activity of coumarin and 4-hydroxycoumarin in the trinitrobenzensulphonic acid model of rat colitis. Biol Pharm Bull 31:1343–1350CrossRefGoogle Scholar
  5. 5.
    Hagenlocher Y, Hösel A, Bischoff SC, Lorentz A (2016) Cinnamon extract reduces symptoms, inflammatory mediators and mast cell markers in murine IL-10–/– colitis. J Nutr Biochem 30:85–92CrossRefGoogle Scholar
  6. 6.
    Azuma T, Shigeshiro M, Kodama M, Tanabe S, Suzuki T (2013) Supplemental naringenin prevents intestinal barrier defects and inflammation in colitis mice. J Nutr 143:827–834CrossRefGoogle Scholar
  7. 7.
    Burke JP, Mulsow JJ, O’Keane C, Docherty NG (2007) Fibrogenesis in Crohn’s disease. Am J Gastroenterol 102:439–448CrossRefGoogle Scholar
  8. 8.
    Carter MJ, Lobo AJ, Travis SP, Section IBD (2004) British Society of Gastroenterology. Guidelines for management of inflammatory bowel disease in adults. Gut 53:V1–V16CrossRefGoogle Scholar
  9. 9.
    Regan MC, Flavin BM, Fitzpatrick JM, O’Connell PR (2000) Stricture formation in Crohn’s Disease—the role of intestinal fibroblasts. Ann Surg 231:46–50CrossRefGoogle Scholar
  10. 10.
    Gaydou EM, Bianchini J, Randriamiharisoa RP (1987) Orange and mandarin peel oils differentiation using polymethoxylated flavone composition. J Agric Food Chem 35:525–529CrossRefGoogle Scholar
  11. 11.
    Dugo P, Mondello L, Dugo L, Stancanelli R, Dugo G (2000) LC-MS for the identification of oxygen heterocyclic compounds in citrus essential oils. J Pharm Biomed Anal 24:147–154CrossRefGoogle Scholar
  12. 12.
    Evans M, Sharma P, Guthrie N (2004) Bioavailability of citrus polymethoxylated flavones and their biological role in metabolic syndrome and hyperlipidemia. Readings Adv Pharmacokinet—Theory, Methods Appl, pp 267–85Google Scholar
  13. 13.
    Seki T, Kamiya T, Furukawa K, Azumi M, Ishizuka S, Takayama S et al (2013) Nobiletin-rich Citrus reticulate peels, a kampo medicine for Alzheimer’s disease: a case series. Geriatr Gerontol Int 13:236–238CrossRefGoogle Scholar
  14. 14.
    Tang MX, Ogawa K, Asamoto M, Chewonarin T, Suzuki S, Tanaka T et al (2011) Effects of nobiletin on PhIP-induced prostate and colon carcinogenesis in F344 rats. Nutr Cancer 63:227–233CrossRefGoogle Scholar
  15. 15.
    Wu YQ, Zhou CH, Tao J, Li SN (2006) Antagonistic effects of nobiletin, a polymethoxyflavonoid, on eosinophilic airway inflammation of asthmatic rats and relevant mechanisms. Life Sci 78:2689–2696CrossRefGoogle Scholar
  16. 16.
    Guo S, Qiu P, Xu G, Wu X, Dong P, Yang G et al (2012) Synergistic anti-inflammatory effects of nobiletin and sulforaphane in lipopolysaccharide-stimulated RAW 264.7 cells. J Agric Food Chem 60:2157–2164CrossRefGoogle Scholar
  17. 17.
    Murakami A, Nakamura Y, Torikai K, Stress O, Promotion T, Tanaka T et al (2000) Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res 60:5059–5066Google Scholar
  18. 18.
    Wu Y, Song M, Rakariyatham K, Zheng J, Guo S, Tang Z et al (2015) Anti-inflammatory effects of 4′-demethylnobiletin, a major metabolite of nobiletin. J Funct Foods 19:278–287CrossRefGoogle Scholar
  19. 19.
    Li W, Wang X, Niu X, Zhang H, He Z, Wang Y et al (2016) Protective effects of nobiletin against endotoxic shock in mice through inhibiting TNF-α, IL-6, and HMGB1 and regulating NF-κB pathway. Inflammation 39:786–797CrossRefGoogle Scholar
  20. 20.
    Hagenlocher Y, Feilhauer K, Schäffer M, Bischoff SC, Lorentz A (2017) Citrus peel polymethoxyflavones nobiletin and tangeretin suppress LPS- and IgE-mediated activation of human intestinal mast cells. Eur J Nutr 56:1609–1620CrossRefGoogle Scholar
  21. 21.
    Xiong Y, Chen D, Yu C, Lv B, Peng J, Wang J et al (2015) Citrus nobiletin ameliorates experimental colitis by reducing inflammation and restoring impaired intestinal barrier function. Mol Nutr Food Res 59:829–842CrossRefGoogle Scholar
  22. 22.
    Rieder F, Kessler S, Sans M, Fiocchi C (2012) Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease. Am J Physiol Gastrointest Liver Physiol 303:G786–G801CrossRefGoogle Scholar
  23. 23.
    Lorentz A, Sellge G, Bischoff SC (2015) Isolation and characterization of human intestinal mast cells. Methods Mol Biol 1220:163–177CrossRefGoogle Scholar
  24. 24.
    Sellge G, Lorentz A, Gebhardt T, Levi-Schaffer F et al (2004) Human intestinal fibroblasts prevent apoptosis in human intestinal mast cells by a mechanism independent of stem cell factor, IL-3, IL-4, and nerve growth factor. J Immunol 172:260–267CrossRefGoogle Scholar
  25. 25.
    Lund PK, Zuniga CC (2001) Intestinal fibrosis in human and experimental inflammatory bowel disease. Curr Opin Gastroenterol 17:318–323CrossRefGoogle Scholar
  26. 26.
    Jacob C, Yang PC, Darmoul D, Amadesi S, Saito T, Cottrell GS et al (2005) Mast cell tryptase controls paracellular permeability of the intestine. Role of protease activated receprot 2 and beta-arrestins. J Biol Chem 280:31936–31948CrossRefGoogle Scholar
  27. 27.
    Chichlowski M, Westwood GS, Abraham SN, Hale LP (2010) Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10 deficient mice. PLoS One 5:e12220CrossRefGoogle Scholar
  28. 28.
    Latella G, Sferra R, Speca S, Vetuschi A, Gaudio E (2013) Can we prevent, reduce or reverse intestinal fibrosis in IBD. Eur Rev Med Pharmacol Sci 17:1283–1304Google Scholar
  29. 29.
    Holgersen K, Kvist PH, Markholst H, Hansen AK, Holm TL (2014) Characterisation of enterocolitis in the piroxicam-accelerated interleukin-10 knock out mouse—a model mimicking inflammatory bowel disease. J Crohn’s Colitis 8:147–160CrossRefGoogle Scholar
  30. 30.
    Hemler ME (1990) VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol 8:365–400CrossRefGoogle Scholar
  31. 31.
    Krieglstein CF, Cerwinka WH, Sprague AG, Laroux FS, Grisham MB, Koteliansky VE et al (2002) Collagen-binding integrin alpha 1 beta 1 regulates intestinal inflammation in experimental colitis. J Clin Invest 110:1773–1782CrossRefGoogle Scholar
  32. 32.
    Nykvist P, Tu H, Ivaska J, Käpylä J, Pihlajaniemi T, Heino J (2000) Distinct recognition of collagen subtypes by α1β1 and α2β1 integrins. α1β1 mediates cell adhesion to type XIII collagen. J Biol Chem 275:8255–8261CrossRefGoogle Scholar
  33. 33.
    Rieder F, Fiocchi C (2009) Intestinal fibrosis in IBD—a dynamic, multifactorial process. Nat Rev Gastroenterol Hepatol 6:28–35CrossRefGoogle Scholar
  34. 34.
    Dennis J, Meehan DT, Delimont D, Zallocchi M, Perry GA, O’Brien S et al (2010) Collagen XIII induced in vascular endothelium mediates α1β1 integrin-dependent transmigration of monocytes in renal fibrosis. Am J Pathol 177:2527–2540CrossRefGoogle Scholar
  35. 35.
    Choi SY, Hwang JH, Ko HC, Park JG, Kim SJ (2007) Nobiletin from citrus peel inhibits the DNA-binding activity of NF-κB and ROS production in LPS-activated RAW 264.7 cells. J Ethn Pharmacol 113:149–155Google Scholar
  36. 36.
    Choi SY, Ko HC, Ko SY, Hwang JH, Park JG, Kang SH, Han SH, Yun SH, Kim SJ (2007) Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol Pharm Bull 30:772–778CrossRefGoogle Scholar
  37. 37.
    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 Pharmacaol 65:2065–2071CrossRefGoogle Scholar
  38. 38.
    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 unshiu in rat primary astrocytes. Biosci Biotechnol Biochem 76:1843–1848CrossRefGoogle Scholar
  39. 39.
    Hagenlocher Y, Bergheim I, Zacheja S, Schäffer M, Bischoff SC, Lorentz A (2013) Cinnamon extract inhibits degranulation and de novo synthesis of inflammatory mediators in mast cells. Allergy 68:490–497CrossRefGoogle Scholar
  40. 40.
    Hagenlocher Y, Satzinger S, Civelek M, Feilhauer K, Köninger J, Bischoff SC, Lorentz A (2017) Cinnamon reduces inflammatory response in intestinal fibroblasts in vitro and fibrosis in vivo. Mol Nutr Food Res.  https://doi.org/10.1002/mnfr.201601085 (Epub 2017 May 12) Google Scholar
  41. 41.
    Azuma T, Shigeshiro M, Kodama M, Tanabe S, Suzuki T (2013) Supplemental naringenin prevents intestinal barrier defects and inflammation in colitic mice 1–3. J Nutr 143:827–834CrossRefGoogle Scholar
  42. 42.
    Xu L, Yang Z, Li P, Zhou Y (2009) Modulating effect of Hesperidin on experimental murine colitis induced by dextran sulfate sodium. Phytomedicine 16:989–995CrossRefGoogle Scholar
  43. 43.
    Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W (1993) Interleukin-10 deficient mice develop chronic enterocolitis. Cell 75:263–274CrossRefGoogle Scholar
  44. 44.
    Rijnierse A, Nijkamp FP, Kraneveld AD (2007) Mast cells and nerves tickle in the tummy. Implications for inflammatory bowel disease and irritable bowel syndrome. Pharmacol Ther 116:207–235CrossRefGoogle Scholar
  45. 45.
    Bischoff SC (2016) Mast cells in gastrointestinal disorders. Eur J Pharmacol 778:139–145CrossRefGoogle Scholar
  46. 46.
    Menozzi A, Pozzoli C, Poli E, Lazzaretti M, Grandi D, Coruzzi G (2006) Long-term study of TNBS-induced colitis in rats: focus on mast cells. Inflamm Res 55:416–422CrossRefGoogle Scholar
  47. 47.
    He SH (2004) Key role of mast cells and their major secretory products in inflammatory bowel disease. World J Gastroenterol 10:309–318CrossRefGoogle Scholar
  48. 48.
    Jacob C, Yang PC, Darmoul D, Amadesi S, Saito T, Cottrell GS et al (2005) Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins. J Biol Chem 280:31936–31948CrossRefGoogle Scholar
  49. 49.
    Polukort SH, Rovatti J, Carlson L, Thompson C, Ser-Dolansky J, Kinney SR, Schneider SS, Mathias CB (2016) IL-10 enhances IgE-mediated mast cell responses and is essential for the development of experimental food allergy in IL-10-deficient mice. J Immunol 196:4865–4876CrossRefGoogle Scholar
  50. 50.
    Adedara IA, Ajayi BO, Awogbindin IO, Farombi EO (2017) Interactive effects of ethanol on ulcerative colitis and its associated testicular dysfunction in pubertal BALB/c mice. Alcohol 64:65–75CrossRefGoogle Scholar
  51. 51.
    Speca S, Rousseaux C, Dubuquoy C, Rieder F, Vetuschi A, Sferra R et al (2016) The novel PPARγ modulator GED-0507-34 Levo ameliorates inflammation-driven intestinal fibrosis. Inflamm Bowl Dis 22:279–292CrossRefGoogle Scholar
  52. 52.
    Suzuki K, Sun X, Nagata M, Kawase T, Yamaguchi H, Sukumaran V et al (2011) Analysis of intestinal fibrosis in chronic colitis in mice induced by dextran sulfate sodium. Pathol Int 61:228–238CrossRefGoogle Scholar
  53. 53.
    Zhang N, Yang Z, Xiang SZ, Jin YG, Wei WY, Bian ZY et al (2016) Nobiletin attenuates cardiac dysfunction, oxidative stress, and inflammatory in streptozotocin: induced diabetic cardiomyopathy. Mol Cell Biochem 417:87–96CrossRefGoogle Scholar
  54. 54.
    Lim SW, Lee DR, Choi BK, Kim HS, Yang SH, Suh JW et al (2016) Protective effects of a polymethoxy flavonoids-rich Citrus aurantium peel extract on liver fibrosis induced by bile duct ligation in mice. Asian Pac J Trop Med 9:1158–1164CrossRefGoogle Scholar
  55. 55.
    Lee MH, Yoon S, Moon JO (2004) The flavonoid naringenin inhibits dimethylnitrosamine-induced liver damage in rats. Biol Pharm Bull 27:72–76Google Scholar
  56. 56.
    Schulzke JD, Ploeger S, Amasheh M, Fromm A, Zeissig S, Troeger H et al (2009) Epithelial tight junctions in intestinal inflammation. Ann N Y Acad Sci 1165:294–300CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Yvonne Hagenlocher
    • 1
  • Sonja Gommeringer
    • 1
  • Anna Held
    • 1
  • Katharina Feilhauer
    • 2
  • Jörg Köninger
    • 2
  • Stephan C. Bischoff
    • 1
  • Axel Lorentz
    • 1
    Email author
  1. 1.Department of Nutritional MedicineUniversity of HohenheimStuttgartGermany
  2. 2.Clinic for Visceral SurgeryKatharinenhospitalStuttgartGermany

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