Browse > Article
http://dx.doi.org/10.5009/gnl18221

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

Song, Chin-Hee (Department of Internal Medicine, Seoul National University Bundang Hospital)
Kim, Nayoung (Department of Internal Medicine, Seoul National University Bundang Hospital)
Sohn, Sung Hwa (Department of Internal Medicine, Seoul National University Bundang Hospital)
Lee, Sun Min (Department of Internal Medicine, Seoul National University Bundang Hospital)
Nam, Ryoung Hee (Department of Internal Medicine, Seoul National University Bundang Hospital)
Na, Hee Young (Department of Pathology, Seoul National University Bundang Hospital)
Lee, Dong Ho (Department of Internal Medicine, Seoul National University Bundang Hospital)
Surh, Young-Joon (Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy)
Publication Information
Gut and Liver / v.12, no.6, 2018 , pp. 682-693 More about this Journal
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 $17{\beta}$-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-${\kappa}B$, iNOS, and COX-2) was increased by AOM/DSS-treatment and ameliorated by E2. Conclusions: E2 acts through the estrogen receptor ${\beta}$ 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.
Keywords
AOM/DSS colitis mouse model; Permeability; Tight junction; Inflammation; Estrogen;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Van der Sluis M, De Koning BA, De Bruijn AC, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 2006;131:117-129.   DOI
2 Tadesse S, Corner G, Dhima E, et al. MUC2 mucin deficiency alters inflammatory and metabolic pathways in the mouse intestinal mucosa. Oncotarget 2017;8:71456-71470.
3 Hsu HP, Lai MD, Lee JC, et al. Mucin 2 silencing promotes colon cancer metastasis through interleukin-6 signaling. Sci Rep 2017;7:5823.   DOI
4 Dhanisha SS, Guruvayoorappan C, Drishya S, Abeesh P. Mucins: structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets. Crit Rev Oncol Hematol 2018;122:98-122.   DOI
5 Andrianifahanana M, Moniaux N, Batra SK. Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases. Biochim Biophys Acta 2006;1765:189-222.
6 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7-30.   DOI
7 Jung KW, Won YJ, Oh CM, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2014. Cancer Res Treat 2017;49:292-305.   DOI
8 Vetrano S, Rescigno M, Cera MR, et al. Unique role of junctional adhesion molecule-A in maintaining mucosal homeostasis in inflammatory bowel disease. Gastroenterology 2008;135:173-184.   DOI
9 Fischer BM, Cuellar JG, Diehl ML, et al. Neutrophil elastase increases MUC4 expression in normal human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2003;284:L671-L679.   DOI
10 Nusrat A, Turner JR, Madara JL. 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 2000;279:G851-G857.   DOI
11 Ueda J, Semba S, Chiba H, et al. Heterogeneous expression of claudin-4 in human colorectal cancer: decreased claudin-4 expression at the invasive front correlates cancer invasion and metastasis. Pathobiology 2007;74:32-41.   DOI
12 Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 2009;1:a000034.
13 Popivanova BK, Kitamura K, Wu Y, et al. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 2008;118:560-570.
14 Grivennikov S, Karin E, Terzic J, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitisassociated cancer. Cancer Cell 2009;15:103-113.   DOI
15 Tanaka T, Kohno H, Suzuki R, Yamada Y, Sugie S, Mori H. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci 2003;94:965-973.   DOI
16 Kim JJ, Kim N, Park JH, et al. Comparison of tight junction protein-related gene mRNA expression levels between male and female gastroesophageal reflux disease patients. Gut Liver 2018;12:411-419.   DOI
17 Sun SC. Non-canonical NF-kappaB signaling pathway. Cell Res 2011;21:71-85.   DOI
18 Pai S, Thomas R. Immune deficiency or hyperactivity-NF-kappaB illuminates autoimmunity. J Autoimmun 2008;31:245-251.   DOI
19 Thaker AI, Shaker A, Rao MS, Ciorba MA. Modeling colitisassociated cancer with azoxymethane (AOM) and dextran sulfate sodium (DSS). J Vis Exp 2012;(67):4100.
20 Suzuki R, Kohno H, Sugie S, Tanaka T. Sequential observations on the occurrence of preneoplastic and neoplastic lesions in mouse colon treated with azoxymethane and dextran sodium sulfate. Cancer Sci 2004;95:721-727.   DOI
21 Tardieu D, Jaeg JP, Cadet J, Embvani E, Corpet DE, Petit C. Dextran sulfate enhances the level of an oxidative DNA damage biomarker, 8-oxo-7,8-dihydro-2'-deoxyguanosine, in rat colonic mucosa. Cancer Lett 1998;134:1-5.   DOI
22 De Robertis M, Massi E, Poeta ML, et al. The AOM/DSS murine model for the study of colon carcinogenesis: from pathways to diagnosis and therapy studies. J Carcinog 2011;10:9.   DOI
23 Suzuki R, Kohno H, Sugie S, Nakagama H, Tanaka T. Strain differences in the susceptibility to azoxymethane and dextran sodium sulfate-induced colon carcinogenesis in mice. Carcinogenesis 2006;27:162-169.
24 Danese S, Malesci A, Vetrano S. Colitis-associated cancer: the dark side of inflammatory bowel disease. Gut 2011;60:1609-1610.   DOI
25 Greten FR, Eckmann L, Greten TF, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004;118:285-296.   DOI
26 Liu T, Zhang L, Joo D, Sun SC. NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2017;2:17023.   DOI
27 Viennois E, Chen F, Merlin D. NF-kappaB pathway in colitisassociated cancers. Transl Gastrointest Cancer 2013;2:21-29.
28 Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor kappa B inflammatory bowel disease. Gut 1998;42:477-484.   DOI
29 Karban AS, Okazaki T, Panhuysen CI, et al. Functional annotation of a novel $NF{\kappa}B1$ promoter polymorphism that increases risk for ulcerative colitis. Hum Mol Genet 2004;13:35-45.   DOI
30 Atreya I, Atreya R, Neurath MF. NF-kappaB in inflammatory bowel disease. J Intern Med 2008;263:591-596.   DOI
31 Gunal O, Oktar BK, Ozcinar E, Sungur M, Arbak S, Yegen B. Estradiol treatment ameliorates acetic acid-induced gastric and colonic injuries in rats. Inflammation 2003;27:351-359.   DOI
32 Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC. Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr 2011;141:769-776.   DOI
33 Shan M, Gentile M, Yeiser JR, et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 2013;342:447-453.   DOI
34 Johansson ME. Mucus layers in inflammatory bowel disease. Inflamm Bowel Dis 2014;20:2124-2131.   DOI
35 Harnish DC, Albert LM, Leathurby Y, et al. Beneficial effects of estrogen treatment in the HLA-B27 transgenic rat model of inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2004;286:G118-G125.   DOI
36 Fishman JE, Levy G, Alli V, Zheng X, Mole DJ, Deitch EA. The intestinal mucus layer is a critical component of the gut barrier that is damaged during acute pancreatitis. Shock 2014;42:264-270.   DOI
37 Krug SM, Schulzke JD, Fromm M. Tight junction, selective permeability, and related diseases. Semin Cell Dev Biol 2014;36:166-176.   DOI
38 Wehkamp J, Koslowski M, Wang G, Stange EF. Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn's disease. Mucosal Immunol 2008;1 Suppl 1:S67-S74.   DOI
39 Wrzosek L, Miquel S, Noordine ML, et al. 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 2013;11:61.   DOI
40 Groschwitz KR, Hogan SP. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol 2009;124:3-20.   DOI
41 Velcich A, Yang W, Heyer J, et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 2002;295:1726-1729.   DOI
42 Yang K, Popova NV, Yang WC, et al. Interaction of Muc2 and Apc on Wnt signaling and in intestinal tumorigenesis: potential role of chronic inflammation. Cancer Res 2008;68:7313-7322.   DOI
43 Saleiro D, Murillo G, Benya RV, Bissonnette M, Hart J, Mehta RG. Estrogen receptor-beta protects against colitis-associated neoplasia in mice. Int J Cancer 2012;131:2553-2561.   DOI
44 Kennelly R, Kavanagh DO, Hogan AM, Winter DC. Oestrogen and the colon: potential mechanisms for cancer prevention. Lancet Oncol 2008;9:385-391.   DOI
45 Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999;106:574-582.   DOI
46 Campbell-Thompson M, Lynch IJ, Bhardwaj B. Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer. Cancer Res 2001;61:632-640.
47 Lee YJ, Hussain Z, Huh CW, Lee YJ, Park H. Inflammation, impaired motility, and permeability in a guinea pig model of postoperative ileus. J Neurogastroenterol Motil 2018;24:147-158.   DOI
48 Das S, Rachagani S, Sheinin Y, et al. Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer. Oncogene 2016;35:2645-2654.   DOI
49 Lee SH. Intestinal permeability regulation by tight junction: implication on inflammatory bowel diseases. Intest Res 2015;13:11-18.   DOI
50 Gonzalez-Mariscal L, Lechuga S, Garay E. Role of tight junctions in cell proliferation and cancer. Prog Histochem Cytochem 2007;42:1-57.   DOI
51 Kim JJ, Kim N, Choi YJ, Kim JS, Jung HC. Increased TRPV1 and PAR2 mRNA expression levels are associated only with the esophageal reflux symptoms, but not with the extraesophageal reflux symptoms. Medicine (Baltimore) 2016;95:e4387.   DOI
52 Konstantinopoulos PA, Kominea A, Vandoros G, et al. Oestrogen receptor beta (ERbeta) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour's dedifferentiation. Eur J Cancer 2003;39:1251-1258.   DOI
53 Son HJ, Sohn SH, Kim N, et al. Effect of estradiol in an azoxymethane/dextran sulfate sodium-treated mouse model of colorectal cancer: implication for sex difference in colorectal cancer development. Cancer Res Treat. Epub 2018 Aug 1. https://doi.org/10.4143/crt.2018.060.
54 Harris HA. Estrogen receptor-beta: recent lessons from in vivo studies. Mol Endocrinol. 2007;21:1-13.   DOI
55 Grishina I, Fenton A, Sankaran-Walters S. Gender differences, aging and hormonal status in mucosal injury and repair. Aging Dis 2014;5:160-169.
56 Lee SM, Kim N, Son HJ, et al. The effect of sex on the azoxymethane/dextran sulfate sodium-treated mice model of colon cancer. J Cancer Prev 2016;21:271-278.   DOI
57 Yum HW, Zhong X, Park J, et al. Oligonol inhibits dextran sulfate sodium-induced colitis and colonic adenoma formation in mice. Antioxid Redox Signal 2013;19:102-114.   DOI
58 Park YH, Kim N, Shim YK, et al. Adequate dextran sodium sulfateinduced colitis model in mice and effective outcome measurement method. J Cancer Prev 2015;20:260-267.   DOI
59 Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep 2010;12:319-330.   DOI
60 Ghaleb AM, Laroui H, Merlin D, Yang VW. 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 2014;20:811-820.   DOI
61 Son HJ, Kim N, Song CH, Lee SM, Lee HN, Surh YJ. $17{\beta}$-Estradiol reduces inflammation and modulates antioxidant enzymes in colonic epithelial cells. Korean J Intern Med. Epub 2018 Oct 22. https://doi.org/10.3904/kjim.2018.098.
62 Audie JP, Janin A, Porchet N, Copin MC, Gosselin B, Aubert JP. Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization. J Histochem Cytochem 1993;41:1479-1485.   DOI
63 Gum JR Jr, Hicks JW, Toribara NW, Siddiki B, Kim YS. Molecular cloning of human intestinal mucin (MUC2) cDNA: identification of the amino terminus and overall sequence similarity to preprovon Willebrand factor. J Biol Chem 1994;269:2440-2446.
64 Buisine MP, Devisme L, Copin MC, et al. Developmental mucin gene expression in the human respiratory tract. Am J Respir Cell Mol Biol 1999;20:209-218.   DOI