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Effects of 17β-Estradiol on Colonic Permeability and Inflammation in an Azoxymethane/Dextran Sulfate Sodium-Induced Colitis Mouse Model

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Background/Aims: Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBDs) such as ulcerative colitis. This dysfunction is caused by increased permeability and the loss of tight junctions in intestinal epithelial cells. The aim of this study was to investigate whether estradiol treatment reduces colonic permeability, tight junction disruption, and inflammation in an azoxymethane (AOM)/dextran sodium sulfate (DSS) colon cancer mouse model. Methods: The effects of 17β-estradiol (E2) were evaluated in ICR male mice 4 weeks after AOM/DSS treatment. Histological damage was scored by hematoxylin and eosin staining and the levels of the colonic mucosal cytokine myeloperoxidase (MPO) were assessed by enzyme-linked immunosorbent assay (ELISA). To evaluate the effects of E2 on intestinal permeability, tight junctions, and inflammation, we performed quantitative real-time polymerase chain reaction and Western blot analysis. Furthermore, the expression levels of mucin 2 (MUC2) and mucin 4 (MUC4) were measured as target genes for intestinal permeability, whereas zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 4 (CLDN4) served as target genes for the tight junctions. Results: The colitis-mediated induced damage score and MPO activity were reduced by E2 treatment (p<0.05). In addition, the mRNA expression levels of intestinal barrier-related molecules (i.e., MUC2, ZO-1, OCLN, and CLDN4) were decreased by AOM/DSS-treatment; furthermore, this inhibition was rescued by E2 supplementation. The mRNA and protein expression of inflammation-related genes (i.e., KLF4, NF-κB, iNOS, and COX-2) was increased by AOM/DSS-treatment and ameliorated by E2. Conclusions: E2 acts through the estrogen receptor β signaling pathway to elicit anti-inflammatory effects on intestinal barrier by inducing the expression of MUC2 and tight junction molecules and inhibiting pro-inflammatory cytokines.

Abstract

Background/Aims: Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBDs) such as ulcerative colitis. This dysfunction is caused by increased permeability and the loss of tight junctions in intestinal epithelial cells. The aim of this study was to investigate whether estradiol treatment reduces colonic permeability, tight junction disruption, and inflammation in an azoxymethane (AOM)/dextran sodium sulfate (DSS) colon cancer mouse model. Methods: The effects of 17β-estradiol (E2) were evaluated in ICR male mice 4 weeks after AOM/DSS treatment. Histological damage was scored by hematoxylin and eosin staining and the levels of the colonic mucosal cytokine myeloperoxidase (MPO) were assessed by enzyme-linked immunosorbent assay (ELISA). To evaluate the effects of E2 on intestinal permeability, tight junctions, and inflammation, we performed quantitative real-time polymerase chain reaction and Western blot analysis. Furthermore, the expression levels of mucin 2 (MUC2) and mucin 4 (MUC4) were measured as target genes for intestinal permeability, whereas zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 4 (CLDN4) served as target genes for the tight junctions. Results: The colitis-mediated induced damage score and MPO activity were reduced by E2 treatment (p<0.05). In addition, the mRNA expression levels of intestinal barrier-related molecules (i.e., MUC2, ZO-1, OCLN, and CLDN4) were decreased by AOM/DSS-treatment; furthermore, this inhibition was rescued by E2 supplementation. The mRNA and protein expression of inflammation-related genes (i.e., KLF4, NF-κB, iNOS, and COX-2) was increased by AOM/DSS-treatment and ameliorated by E2. Conclusions: E2 acts through the estrogen receptor β signaling pathway to elicit anti-inflammatory effects on intestinal barrier by inducing the expression of MUC2 and tight junction molecules and inhibiting pro-inflammatory cytokines.

참고문헌 (64)

  1. Siegel RL, "Cancer statistics, 2018", CA Cancer J Clin, 68, pp.7~30 (2018)
  2. 정규원, "Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2014", Cancer Research and Treatment, 49(2), pp.292~305 (2017), 대한암학회
  3. Danese S, "Colitis-associated cancer: the dark side of inflammatory bowel disease", Gut, 60, pp.1609~1610 (2011)
  4. Popivanova BK, "Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis", J Clin Invest, 118, pp.560~570 (2008)
  5. Grivennikov S, "IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitisassociated cancer", Cancer Cell, 15, pp.103~113 (2009)
  6. Tanaka T, "A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate", Cancer Sci, 94, pp.965~973 (2003)
  7. Suzuki R, "Sequential observations on the occurrence of preneoplastic and neoplastic lesions in mouse colon treated with azoxymethane and dextran sodium sulfate", Cancer Sci, 95, pp.721~727 (2004)
  8. Thaker AI, "Modeling colitisassociated cancer with azoxymethane (AOM) and dextran sulfate sodium (DSS)", J Vis Exp, (67), pp.4100~ (2012)
  9. Tardieu D, "Dextran sulfate enhances the level of an oxidative DNA damage biomarker, 8-oxo-7,8-dihydro-2’-deoxyguanosine, in rat colonic mucosa", Cancer Lett, 134, pp.1~5 (1998)
  10. De Robertis M, "The AOM", DSS murine model for the study of colon carcinogenesis: from pathways to diagnosis and therapy studies, 2011, pp.10, 9~
  11. Suzuki R, "Strain differences in the susceptibility to azoxymethane and dextran sodium sulfate-induced colon carcinogenesis in mice", Carcinogenesis, 27, pp.162~169 (2006)
  12. Shan M, "Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals", Science, 342, pp.447~453 (2013)
  13. Johansson ME, "Mucus layers in inflammatory bowel disease", Inflamm Bowel Dis, 20, pp.2124~2131 (2014)
  14. Fishman JE, "The intestinal mucus layer is a critical component of the gut barrier that is damaged during acute pancreatitis", Shock, 42, pp.264~270 (2014)
  15. Krug SM, "Tight junction, selective permeability, and related diseases", Semin Cell Dev Biol, 36, pp.166~176 (2014)
  16. Wehkamp J, "Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn’s disease", Mucosal Immunol, 1(Suppl 1), pp.S67~S74 (2008)
  17. Wrzosek L, "Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent", BMC Biol, 11, pp.61~ (2013)
  18. Ulluwishewa D, "Regulation of tight junction permeability by intestinal bacteria and dietary components", J Nutr, 141, pp.769~776 (2011)
  19. Groschwitz KR, "Intestinal barrier function: molecular regulation and disease pathogenesis", J Allergy Clin Immunol, 124, pp.3~20 (2009)
  20. Velcich A, "Colorectal cancer in mice genetically deficient in the mucin Muc2", Science, 295, pp.1726~1729 (2002)
  21. Yang K, "Interaction of Muc2 and Apc on Wnt signaling and in intestinal tumorigenesis: potential role of chronic inflammation", Cancer Res, 68, pp.7313~7322 (2008)
  22. Das S, "Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer", Oncogene, 35, pp.2645~2654 (2016)
  23. 이성희, "Intestinal Permeability Regulation by Tight Junction: Implication on Inflammatory Bowel Diseases", Intestinal research, 13(1), pp.11~18 (2015), 대한장연구학회[DOI]
  24. González-Mariscal L, "Role of tight junctions in cell proliferation and cancer", Prog Histochem Cytochem, 42, pp.1~57 (2007)
  25. Yoo Jin Lee, "Inflammation, Impaired Motility, and Permeability in a Guinea Pig Model of Postoperative Ileus", Journal of Neurogastroenterology and Motility (JNM), 24(1), pp.147~158 (2018), 대한소화기 기능성질환∙운동학회[DOI]
  26. Kim JJ, "Increased TRPV1 and PAR2 mRNA expression levels are associated only with the esophageal reflux symptoms, but not with the extraesophageal reflux symptoms", Medicine (Baltimore), 95, pp.e4387~ (2016)
  27. Konstantinopoulos PA, "Oestrogen receptor beta (ERbeta) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour’s dedifferentiation", Eur J Cancer, 39, pp.1251~1258 (2003)
  28. Hee Jin Son, "Effect of Estradiol in an Azoxymethane", Dextran Sulfate Sodium-Treated Mouse Model of Colorectal Cancer: Implication for Sex Difference in Colorectal Cancer Development, 2018, ~[DOI]
  29. Harris HA, "Estrogen receptor-beta : recent lessons from in vivo studies", Mol Endocrinol, 21, pp.1~13 (2007)
  30. Sun Min Lee, "The Effect of Sex on the Azoxymethane", Dextran Sulfate Sodium-treated Mice Model of Colon Cancer, 2016, pp.21(4), 271~278[DOI]
  31. Yum HW, "Oligonol inhibits dextran sulfate sodium-induced colitis and colonic adenoma formation in mice", Antioxid Redox Signal, 19, pp.102~114 (2013)
  32. Yo Han Park, "Adequate Dextran Sodium Sulfate-induced Colitis Model in Mice and Effective Outcome Measurement Method", 대한암예방학회지, 20(4), pp.260~267 (2015), 대한암예방학회
  33. Kim YS, "Intestinal goblet cells and mucins in health and disease: recent insights and progress", Curr Gastroenterol Rep, 12, pp.319~330 (2010)
  34. Ghaleb AM, "Genetic deletion of Klf4 in the mouse intestinal epithelium ameliorates dextran sodium sulfate-induced colitis by modulating the NF-kappaB pathway inflammatory response", Inflamm Bowel Dis, 20, pp.811~820 (2014)
  35. Grishina I, "Gender differences, aging and hormonal status in mucosal injury and repair", Aging Dis, 5, pp.160~169 (2014)
  36. Son HJ, "17β-Estradiol reduces inflammation and modulates antioxidant enzymes in colonic epithelial cells", Korean J Intern Med (2018)[DOI]
  37. Audie JP, "Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization", J Histochem Cytochem, 41, pp.1479~1485 (1993)
  38. Buisine MP, "Developmental mucin gene expression in the human respiratory tract", Am J Respir Cell Mol Biol, 20, pp.209~218 (1999)
  39. Gum JR Jr, "Molecular cloning of human intestinal mucin (MUC2) cDNA: identification of the amino terminus and overall sequence similarity to preprovon Willebrand factor", J Biol Chem, 269, pp.2440~2446 (1994)
  40. Van der Sluis M, "Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection", Gastroenterology, 131, pp.117~129 (2006)
  41. Tadesse S, "MUC2 mucin deficiency alters inflammatory and metabolic pathways in the mouse intestinal mucosa", Oncotarget, 8, pp.71456~71470 (2017)
  42. Hsu HP, "Mucin 2 silencing promotes colon cancer metastasis through interleukin-6 signaling", Sci Rep, 7, pp.5823~ (2017)
  43. Dhanisha SS, "Mucins: structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets", Crit Rev Oncol Hematol, 122, pp.98~122 (2018)
  44. Andrianifahanana M, "Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases", Biochim Biophys Acta, 1765, pp.189~222 (2006)
  45. Fischer BM, "Neutrophil elastase increases MUC4 expression in normal human bronchial epithelial cells", Am J Physiol Lung Cell Mol Physiol, 284, pp.L671~L679 (2003)
  46. Nusrat A, "Molecular physiology and pathophysiology of tight junctions. IV. Regulation of tight junctions by extracellular stimuli: nutrients, cytokines, and immune cells", Am J Physiol Gastrointest Liver Physiol, 279, pp.G851~G857 (2000)
  47. Vetrano S, "Unique role of junctional adhesion molecule-A in maintaining mucosal homeostasis in inflammatory bowel disease", Gastroenterology, 135, pp.173~184 (2008)
  48. Ueda J, "Heterogeneous expression of claudin-4 in human colorectal cancer: decreased claudin-4 expression at the invasive front correlates cancer invasion and metastasis", Pathobiology, 74, pp.32~41 (2007)
  49. Jin Joo Kim, "Comparison of Tight Junction Protein-Related Gene mRNA Expression Levels between Male and Female Gastroesophageal Reflux Disease Patients", Gut and Liver, 12(4), pp.411~419 (2018), 거트앤리버 소화기연관학회협의회
  50. Sun SC, "Non-canonical NF-kappaB signaling pathway", Cell Res, 21, pp.71~85 (2011)
  51. Oeckinghaus A, "The NF-kappaB family of transcription factors and its regulation", Cold Spring Harb Perspect Biol, 1, pp.a000034~ (2009)
  52. Pai S, "Immune deficiency or hyperactivity-NF-kappaB illuminates autoimmunity", J Autoimmun, 31, pp.245~251 (2008)
  53. Liu T, "NF-kappaB signaling in inflammation", Signal Transduct Target Ther, 2, pp.17023~ (2017)
  54. Viennois E, "NF-kappaB pathway in colitisassociated cancers", Transl Gastrointest Cancer, 2, pp.21~29 (2013)
  55. Schreiber S, "Activation of nuclear factor kappa B inflammatory bowel disease", Gut, 42, pp.477~484 (1998)
  56. Greten FR, "IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer", Cell, 118, pp.285~296 (2004)
  57. Karban AS, "Functional annotation of a novel NFκB1 promoter polymorphism that increases risk for ulcerative colitis", Hum Mol Genet, 13, pp.35~45 (2004)
  58. Atreya I, "NF-kappaB in inflammatory bowel disease", J Intern Med, 263, pp.591~596 (2008)
  59. Günal O, "Estradiol treatment ameliorates acetic acid-induced gastric and colonic injuries in rats", Inflammation, 27, pp.351~359 (2003)
  60. Harnish DC, "Beneficial effects of estrogen treatment in the HLA-B27 transgenic rat model of inflammatory bowel disease", Am J Physiol Gastrointest Liver Physiol, 286, pp.G118~G125 (2004)
  61. Kennelly R, "Oestrogen and the colon: potential mechanisms for cancer prevention", Lancet Oncol, 9, pp.385~391 (2008)
  62. Grodstein F, "Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis", Am J Med, 106, pp.574~582 (1999)
  63. Campbell-Thompson M, "Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer", Cancer Res, 61, pp.632~640 (2001)
  64. Saleiro D, "Estrogen receptor-beta protects against colitis-associated neoplasia in mice", Int J Cancer, 131, pp.2553~2561 (2012)

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