Aryl hydrocarbon receptor activation maintained the intestinal epithelial barrier function through Notch1 dependent signaling pathway

Liu,Zhongze; Li,Liangzi; Chen,Weigang; Wang,Qimeng; Xiao,Weidong; Ma,Yuanhang; Sheng,Baifa; Li,Xiang; Sun,Lihua; Yu,Min; Yang,Hua

doi:10.3892/ijmm.2017.3341

Aryl hydrocarbon receptor activation maintained the intestinal epithelial barrier function through Notch1 dependent signaling pathway

Authors:
- Zhongze Liu
- Liangzi Li
- Weigang Chen
- Qimeng Wang
- Weidong Xiao
- Yuanhang Ma
- Baifa Sheng
- Xiang Li
- Lihua Sun
- Min Yu
- Hua Yang
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Affiliations: Department of General Surgery, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, P.R. China
Published online on: December 22, 2017 https://doi.org/10.3892/ijmm.2017.3341
Pages: 1560-1572
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Intestinal ischemia/reperfusion (I/R) induces disruption of the intestinal barrier function. Aryl hydrocarbon receptor (AhR) has a vital role in maintaining the intestinal barrier function. However, the precise mechanism by which AhR maintains intestinal barrier function remains unclear. Notch1 signaling is downstream of AhR, and has also been reported to have a role in the development of tight junctions (TJs) and maintenance of intestinal homeostasis. Therefore, we hypothesized that AhR activation may attenuate the intestinal barrier dysfunction through increased activation of Notch1 signaling. Adult C57BL/6J mice were divided into three groups: Sham, I/R and I/R + 6-formylindolo(3,2-b)carbazole (Ficz) groups. Mice were sacrificed after I/R for 6 h and the intestine was harvested for histological examination, mRNA and protein content analysis, and mucosal permeability investigation. Additionally, a hypoxic Caco‑2 cell culture model was used to evaluate the role of AhR‑Notch1 signaling in the development of TJs and epithelial permeability in vitro. The AhR‑Notch1 signaling components and TJ proteins were assessed by reverse transcription‑quantitative polymerase chain reaction, western blotting, immunohistochemistry or immunofluorescence staining. Epithelial permeability was detected by transepithelium electrical resistance. The data demonstrated that Ficz significantly attenuated the intestinal tissue damage and the disrupted distribution of TJs, increased the expression of TJ proteins, reversed the decrease in TER and upregulated epithelial Notch1 signaling following intestinal I/R in vivo and hypoxia in vitro. Furthermore, inhibition of Notch1 signaling by N‑[N‑(3,5‑difluorophenacetyl)‑L‑alanyl]‑S‑phenylglycine t‑butyl ester (inhibitor of Notch signaling) counteracted the effects of Ficz on the development of TJs in hypoxic Caco‑2 cells. In conclusion, AhR activation ameliorated epithelial barrier dysfunction following intestinal I/R and hypoxia through upregulation of Notch1 signaling, which suggests that AhR may be a potential pharmaceutical agent to combat this condition.

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1	Arda-Pirincci P and Bolkent S: The role of epidermal growth factor in prevention of oxidative injury and apoptosis induced by intestinal ischemia/reperfusion in rats. Acta Histochem. 116:167–175. 2014. View Article : Google Scholar
2	Granger DN and Korthuis RJ: Physiologic mechanisms of post-ischemic tissue injury. Annu Rev Physiol. 57:311–332. 1995. View Article : Google Scholar
3	Matthijsen RA, Derikx JP, Kuipers D, van Dam RM, Dejong CH and Buurman WA: Enterocyte shedding and epithelial lining repair following ischemia of the human small intestine attenuate inflammation. PLoS One. 4:e70452009. View Article : Google Scholar : PubMed/NCBI
4	Lee SH: Intestinal permeability regulation by tight junction: implication on inflammatory bowel diseases. Intest Res. 13:11–18. 2015. View Article : Google Scholar : PubMed/NCBI
5	Yang Y, Qiu Y, Wang W, Xiao W, Liang H, Zhang C and Yang H, Teitelbaum DH, Sun LH and Yang H: Adenosine A2B receptor modulates intestinal barrier function under hypoxic and ischemia/reperfusion conditions. Int J Clin Exp Pathol. 7:2006–2018. 2014.PubMed/NCBI
6	Cai Y, Wang W, Liang H, Sun L, Teitelbaum DH and Yang H: Keratinocyte growth factor improves epithelial structure and function in a mouse model of intestinal ischemia/reperfusion. PLoS One. 7:e447722012. View Article : Google Scholar : PubMed/NCBI
7	Xie G, Peng Z and Raufman JP: Src-mediated aryl hydrocarbon and epidermal growth factor receptor cross talk stimulates colon cancer cell proliferation. Am J Physiol Gastrointest Liver Physiol. 302:G1006–G1015. 2012. View Article : Google Scholar : PubMed/NCBI
8	Marlowe JL, Fan Y, Chang X, Peng L, Knudsen ES, Xia Y and Puga A: The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis. Mol Biol Cell. 19:3263–3271. 2008. View Article : Google Scholar : PubMed/NCBI
9	Mandavia C: TCDD-induced activation of aryl hydrocarbon receptor regulates the skin stem cell population. Med Hypotheses. 84:204–208. 2015. View Article : Google Scholar : PubMed/NCBI
10	Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX and Zhou L: The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity. 36:92–104. 2012. View Article : Google Scholar :
11	Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P, Biancone L, MacDonald TT, Pallone F and Monteleone G: Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology. 141:237–248. 2011. View Article : Google Scholar : PubMed/NCBI
12	Ji T, Xu C, Sun L, Yu M, Peng K, Qiu Y, Xiao W and Yang H: Aryl hydrocarbon receptor activation down-regulates IL-7 and reduces inflammation in a mouse model of DSS-induced colitis. Dig Dis Sci. 60:1958–1966. 2015. View Article : Google Scholar : PubMed/NCBI
13	Qiu J, Guo X, Chen ZM, He L, Sonnenberg GF, Artis D, Fu YX and Zhou L: Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity. 39:386–399. 2013. View Article : Google Scholar : PubMed/NCBI
14	Arsenescu R, Arsenescu V, Zhong J, Nasser M, Melinte R, Dingle RW, Swanson H and de Villiers WJ: Role of the xenobiotic receptor in inflammatory bowel disease. Inflamm Bowel Dis. 17:1149–1162. 2011. View Article : Google Scholar :
15	Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C and Veldhoen M: Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell. 147:629–640. 2011. View Article : Google Scholar : PubMed/NCBI
16	Jing H, Shen G, Wang G, Zhang F, Li Y, Luo F, Yao J and Tian XF: MG132 alleviates liver injury induced by intestinal ischemia/reperfusion in rats: involvement of the AhR and NFκB pathways. J Surg Res. 176:63–73. 2012. View Article : Google Scholar
17	Dahan S, Rabinowitz KM, Martin AP, Berin MC, Unkeless JC and Mayer L: Notch-1 signaling regulates intestinal epithelial barrier function, through interaction with CD4⁺ T cells, in mice and humans. Gastroenterology. 140:550–559. 2011. View Article : Google Scholar
18	Mathern DR, Laitman LE, Hovhannisyan Z, Dunkin D, Farsio S, Malik TJ, Roda G, Chitre A, Iuga AC, Yeretssian G, et al: Mouse and human Notch-1 regulate mucosal immune responses. Mucosal Immunol. 7:995–1005. 2014. View Article : Google Scholar : PubMed/NCBI
19	Chen G, Sun L, Yu M, Meng D, Wang W, Yang Y and Yang H: The Jagged-1/Notch-1/Hes-1 pathway is involved in intestinal adaptation in a massive small bowel resection rat model. Dig Dis Sci. 58:2478–2486. 2013. View Article : Google Scholar : PubMed/NCBI
20	Chen G, Qiu Y, Sun L, Yu M, Wang W, Xiao W, Yang Y, Liu Y, Yang S, Teitelbaum DH, et al: The jagged-2/notch-1/hes-1 pathway is involved in intestinal epithelium regeneration after intestinal ischemia-reperfusion injury. PLoS One. 8:e762742013. View Article : Google Scholar : PubMed/NCBI
21	Lee JS, Cella M, McDonald KG, Garlanda C, Kennedy GD, Nukaya M, Mantovani A, Kopan R, Bradfield CA, Newberry RD, et al: AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat Immunol. 13:144–151. 2011. View Article : Google Scholar : PubMed/NCBI
22	Stevens EA, Mezrich JD and Bradfield CA: The aryl hydrocarbon receptor: a perspective on potential roles in the immune system. Immunology. 127:299–311. 2009. View Article : Google Scholar : PubMed/NCBI
23	Xia M, Viera-Hutchins L, Garcia-Lloret M, Noval Rivas M, Wise P, McGhee SA, Chatila ZK, Daher N, Sioutas C and Chatila TA: Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-Notch signaling cascade. J Allergy Clin Immunol. 136:441–453. 2015. View Article : Google Scholar : PubMed/NCBI
24	Alam MS, Maekawa Y, Kitamura A, Tanigaki K, Yoshimoto T, Kishihara K and Yasutomo K: Notch signaling drives IL-22 secretion in CD4⁺ T cells by stimulating the aryl hydrocarbon receptor. Proc Natl Acad Sci USA. 107:5943–5948. 2010. View Article : Google Scholar
25	Qiu Y, Yu M, Yang Y, Sheng H, Wang W, Sun L, Chen G, Liu Y, Xiao W and Yang H: Disturbance of intraepithelial lymphocytes in a murine model of acute intestinal ischemia/reperfusion. J Mol Histol. 45:217–227. 2014. View Article : Google Scholar
26	Chiu CJ, McArdle AH, Brown R, Scott HJ and Gurd FN: Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg. 101:478–483. 1970. View Article : Google Scholar : PubMed/NCBI
27	Polentarutti BI, Peterson AL, Sjöberg AK, Anderberg EK, Utter LM and Ungell AL: Evaluation of viability of excised rat intestinal segments in the Ussing chamber: investigation of morphology, electrical parameters, and permeability characteristics. Pharm Res. 16:446–454. 1999. View Article : Google Scholar : PubMed/NCBI
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
29	Nebert DW and Roe AL: Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol. 59:65–85. 2000. View Article : Google Scholar
30	Delescluse C, Lemaire G, de Sousa G and Rahmani R: Is CYP1A1 induction always related to AHR signaling pathway. Toxicology. 153:73–82. 2000. View Article : Google Scholar : PubMed/NCBI
31	Chen G, Zhang Z, Cheng Y, Xiao W, Qiu Y, Yu M, Sun L, Wang W, Du G, Gu Y, et al: The canonical Notch signaling was involved in the regulation of intestinal epithelial cells apoptosis after intestinal ischemia/reperfusion injury. Int J Mol Sci. 15:7883–7896. 2014. View Article : Google Scholar : PubMed/NCBI
32	Huang CY, Hsiao JK, Lu YZ, Lee TC and Yu LC: Anti-apoptotic PI3K/Akt signaling by sodium/glucose transporter 1 reduces epithelial barrier damage and bacterial translocation in intestinal ischemia. Lab Invest. 91:294–309. 2011. View Article : Google Scholar
33	Jönsson ME, Franks DG, Woodin BR, Jenny MJ, Garrick RA, Behrendt L, Hahn ME and Stegeman JJ: The tryptophan photo-product 6-formylindolo[3,2-b]carbazole (FICZ) binds multiple AHRs and induces multiple CYP1 genes via AHR2 in zebrafish. Chem Biol Interact. 181:447–454. 2009. View Article : Google Scholar
34	Daniel RA, Cardoso VK, Góis E Jr, Parra RS, Garcia SB, Rocha JJ and Féres O: Effect of hyperbaric oxygen therapy on the intestinal ischemia reperfusion injury. Acta Cir Bras. 26:463–469. 2011. View Article : Google Scholar : PubMed/NCBI
35	Ogando J, Tardáguila M, Díaz-Alderete A, Usategui A, Miranda-Ramos V, Martínez-Herrera DJ, de la Fuente L, García-León MJ, Moreno MC, Escudero S, et al: Notch-regulated miR-223 targets the aryl hydrocarbon receptor pathway and increases cytokine production in macrophages from rheumatoid arthritis patients. Sci Rep. 6:202232016. View Article : Google Scholar : PubMed/NCBI
36	González-Mariscal L, Tapia R and Chamorro D: Crosstalk of tight junction components with signaling pathways. Biochim Biophys Acta. 1778:729–756. 2008. View Article : Google Scholar
37	Pope JL, Bhat AA, Sharma A, Ahmad R, Krishnan M, Washington MK, Beauchamp RD, Singh AB and Dhawan P: Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling. Gut. 63:622–634. 2014. View Article : Google Scholar
38	Movahedan A, Afsharkhamseh N, Sagha HM, Shah JR, Milani BY, Milani FY, Logothetis HD, Chan CC and Djalilian AR: Loss of Notch1 disrupts the barrier repair in the corneal epithelium. PLoS One. 8:e691132013. View Article : Google Scholar : PubMed/NCBI