Top

Published in:

01-09-2011 | Original Article

A Role of the Aryl Hydrocarbon Receptor in Attenuation of Colitis

Authors: Keisuke Furumatsu, Shin Nishiumi, Yuki Kawano, Makoto Ooi, Tomoo Yoshie, Yuuki Shiomi, Hiromu Kutsumi, Hitoshi Ashida, Yoshiaki Fujii-Kuriyama, Takeshi Azuma, Masaru Yoshida

Published in: Digestive Diseases and Sciences | Issue 9/2011

Abstract

Background and Aims

The aryl hydrocarbon receptor (AhR), which is a member of the basic helix-loop-helix/Per-Arnt-Sim homology superfamily, plays an important role in multiple biological functions, and AhR knockout (AhR KO) animals suffer from a variety of organ disorders including a decline in the efficacy of their immune system. In addition, AhR activation is known to aid the maintenance of homeostasis in vivo. In this study, we investigated whether AhR is functionally associated with intestinal immunity.

Methods and Results

In in vivo experiments, it was found that dextran sodium sulfate (DSS)-evoked colitis was more severe in AhR KO mice than in C57BL/6J wild type mice. It was also revealed that the administration of DSS increased the expression levels of AhR and CYP1A1 mRNA in the colon epithelium. In addition, oral administration of β-naphthoflavone (βNF), a non-toxic agonist of AhR, suppressed the pathogenesis of DSS-induced colitis. βNF also attenuated DSS-induced colitis. In cell culture experiments, downregulation of AhR in human colon carcinoma SW480 cells enhanced the inflammatory responses evoked by lipopolysaccharide (LPS), and furthermore, AhR activation attenuated LPS-induced inflammatory responses, suggesting that AhR expressing intestinal epithelial cells are involved in the prevention of colitis.

Conclusions

Our findings about the potential role of AhR activators in epithelial immune regulation aid our understanding of mucosal homeostasis and inflammatory bowl disease (IBD) and suggest that AhR activation has therapeutic value for the treatment of IBD.

Aranda R, Sydora BC, McAllister PL, Binder SW, et al. Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD41, CD45RBhigh T cells to SCID recipients. J Immunol. 1997;158:3464–3473.PubMed

Rath HC, Schultz M, Freitag R, Dieleman LA, et al. Different subsets of enteric bacteria in-duce and perpetuate experimental colitis in rats and mice. Infect Immun. 2001;69:2277–2285.PubMedCrossRef

Mizoguchi A, Mizoguchi E. Inflammatory bowel disease, past, present and future: lessons from animal models. J Gastroenterol. 2008;43:1–17.PubMedCrossRef

Zimmerman NP, Vongsa RA, Wendt MK, Dwinell MB. Chemokines and chemokine receptors in mucosal homeostasis at the intestinal epithelial barrier in inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:1000–1011.PubMedCrossRef

Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest. 2007;117:514–521.PubMedCrossRef

Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, et al. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology. 1990;98:694–702.PubMed

Cooper HS, Murthy SN, Shah RS, Sedergran DJ. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69:238–249.PubMed

Ishida T, Yoshida M, Arita M, Nishitani Y, et al. Resolvin E1, an endogenous lipid mediator derived from eicosapentaenoic acid, prevents dextran sulfate sodium-induced colitis. Inflamm Bowel Dis. 2010;16:87–95.PubMed

Ruyssers NE, De Winter BY, De Man JG, Ruyssers ND, et al. Schistosoma mansoni proteins attenuate gastrointestinal motility disturbances during experimental colitis in mice. World J Gastroenterol. 2010;16:703–712.PubMedCrossRef

10.

Elliott DE, Li J, Blum A, Metwali A, et al. Exposure to schistosome eggs protects mice from TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol. 2003;284:385–391.

11.

Pini M, Gove ME, Fayad R, Cabay RJ, Fantuzzi G. Adiponectin deficiency does not affect development and progression of spontaneous colitis in IL-10 knockout mice. Am J Physiol Gastrointest Liver Physiol. 2009;296:G382–G387.PubMedCrossRef

12.

Paul G, Schäffler A, Neumeier M, Fürst A, et al. Profiling adipocytokine secretion from creeping fat in Crohn’s disease. Inflamm Bowel Dis. 2006;12:471–477.PubMedCrossRef

13.

Denis M, Cuthill S, Wikström AC, Poellinger L, Gustafsson JA. Association of the dioxin receptor with the Mr 90,000 heat shock protein: a structural kinship with the glucocorticoid receptor. Biochem Biophys Res Commun. 1988;155:801–807.PubMedCrossRef

14.

Fujii-Kuriyama Y, Ema M, Mimura J, Sogawa K. Ah receptor: a novel ligand-activated transcription factor. Exp Clin Immunogenet. 1994;1:65–74.

15.

Okino ST, Whitlock JP Jr. The aromatic hydrocarbon receptor, transcription, and endocrine aspects of dioxin action. Vitam Horm. 2000;59:241–264.PubMedCrossRef

16.

Shimada T, Inoue K, Suzuki Y, Kawai T, et al. Arylhydrocarbon receptor-dependent induction of liver and lung cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic hydrocarbons and polychlorinated biphenyls in genetically engineered C57BL/6 J mice. Carcinogenesis. 2002;23:1199–1207.PubMedCrossRef

17.

Mimura J, Yamashita K, Nakamura K, Morita M, et al. Loss of teratogenic response to 2, 3, 7, 8-tetrachlorodibenzop-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells. 1997;2:645–654.PubMedCrossRef

18.

Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, et al. Benzopyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci USA. 2000;97:779–782.PubMedCrossRef

19.

Thatcher TH, Maggirwar SB, Baglole CJ, Lakatos HF, et al. Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB. Am J Pathol. 2007;170:855–864.PubMedCrossRef

20.

Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science. 1995;268:722–726.PubMedCrossRef

21.

Kawajiri K, Kobayashi Y, Ohtake F, Ikuta T, et al. Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands. Proc Natl Acad Sci USA. 2009;106:13481–13486.PubMedCrossRef

22.

Shimada Y, Dewa Y, Ichimura R, Suzuki T, et al. Antioxidant enzymatically modified isoquercitrin suppresses the development of liver preneoplastic lesions in rats induced by beta-naphthoflavone. Toxicology. 2010;268:213–218.PubMedCrossRef

23.

Rhodes JC, Houston JB. Antipyrine metabolite kinetics in phenobarbital and beta-naphthoflavone-induced rats. Drug Metab Dispos. 1983;11:131–136.PubMed

24.

Negishi T, Kato Y, Ooneda O, Mimura J, et al. Effects of aryl hydrocarbon receptor signaling on the modulation of TH1/TH2 balance. J Immunol. 2005;175:7348–7356.PubMed

25.

Gasiewicz TA, Singh KP, Casado FL. The aryl hydrocarbon receptor has an important role in the regulation of hematopoiesis: implications for benzene-induced hematopoietic toxicity. Chem Biol Interact. 2010;184:246–251.PubMedCrossRef

26.

Sekine H, Mimura J, Oshima M, Okawa H, et al. Hypersensitivity of aryl hydrocarbon receptor-deficient mice to lipopolysaccharide-induced septic shock. Mol Cell Biol. 2009;29:6391–6400.PubMedCrossRef

27.

Furness SG, Whelan F. The pleiotropy of dioxin toxicity–xenobiotic misappropriation of the aryl hydrocarbon receptor’s alternative physiological roles. Pharmacol Ther. 2009;124:336–353.PubMedCrossRef

28.

Jux B, Kadow S, Esser C. Langerhans cell maturation and contact hypersensitivity are impaired in aryl hydrocarbon receptor-null mice. J Immunol. 2009;182:6709–6717.PubMedCrossRef

29.

McMillan BJ, Bradfield CA. The aryl hydrocarbon receptor sans xenobiotics: endogenous function in genetic model systems. Mol Pharmacol. 2007;72:487–498.PubMedCrossRef

30.

Teske S, Bohn AA, Hogaboam JP, Lawrence BP. Aryl hydrocarbon receptor targets pathways extrinsic to bone marrow cells to enhance neutrophil recruitment during influenza virus infection. Toxicol Sci. 2008;102:89–99.PubMedCrossRef

31.

Tian Y, Ke S, Denison MS, Rabson AB, Gallo MA. Ah receptor and NF-kappaB interactions, a potential mechanism for dioxin toxicity. J Biol Chem. 1999;274:510–515.PubMedCrossRef

32.

Jensen BA, Leeman RJ, Schlezinger JJ, Sherr DH. Aryl hydrocarbon receptor (AhR) agonists suppress interleukin-6 expression by bone marrow stromal cells an immunotoxicology study. Environ Health. 2003;2:16.PubMedCrossRef

33.

Murray IA, Krishnegowda G, Dinatale BC, Flaveny C, et al. Development of a selective modulator of Aryl hydrocarbon (Ah) receptor activity that exhibits anti-inflammatory properties. Chem Res Toxicol. 2010;23:955–966.PubMedCrossRef

34.

Bankoti J, Rase B, Simones T, Shepherd DM. Functional and phenotypic effects of AhR activation in inflammatory dendritic cells. Toxicol Appl Pharmacol. 2010;246:18–28.PubMedCrossRef

35.

Platzer B, Richter S, Kneidinger D, Waltenberger D, et al. Aryl hydrocarbon receptor activation inhibits in vitro differentiation of human monocytes and Langerhans dendritic cells. J Immunol. 2009;183:66–74.PubMedCrossRef

36.

Kato Y, Negishi T, Furusako S, Mizuguchi K, Mochizuki H. An orally active Th1/Th2 balance modulator, M50367, suppresses Th2 differentiation of naïve Th cell in vitro. Cell Immunol. 2003;224:29–37.PubMedCrossRef

37.

Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci USA. 2008;105:9721–9726.PubMedCrossRef

38.

Zhang L, Ma J, Takeuchi M, Usui Y, et al. Suppression of experimental autoimmune uveoretinitis by inducing differentiation of regulatory T cells via activation of aryl hydrocarbon receptor. Invest Ophthalmol Vis Sci. 2010;51:2109–2117.PubMedCrossRef

39.

Cherayil BJ. Indoleamine 2, 3-dioxygenase in intestinal immunity and inflammation. Inflamm Bowel Dis. 2009;15:1391–1396.PubMedCrossRef

40.

Zheng L, Riehl TE, Stenson WF. Regulation of colonic epithelial repair in mice by Toll-like receptors and hyaluronic acid. Gastroenterology. 2009;137:2041–2051.PubMedCrossRef

41.

Satoh Y, Ishiguro Y, Sakuraba H, Kawaguchi S, et al. Cyclosporine regulates intestinal epithelial apoptosis via TGF-beta-related signaling. Am J Physiol Gastrointest Liver Physiol. 2009;297:G514–G519.PubMedCrossRef

Title: A Role of the Aryl Hydrocarbon Receptor in Attenuation of Colitis
Authors: Keisuke Furumatsu
Shin Nishiumi
Yuki Kawano
Makoto Ooi
Tomoo Yoshie
Yuuki Shiomi
Hiromu Kutsumi
Hitoshi Ashida
Yoshiaki Fujii-Kuriyama
Takeshi Azuma
Masaru Yoshida
Publication date: 01-09-2011
Publisher: Springer US
Published in: Digestive Diseases and Sciences / Issue 9/2011
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-011-1643-9

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background and Aims

Methods and Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 9/2011

Detection of Esophageal Varices Using CT and MRI

A Rare Presentation of an Uncommon Malignancy: Thromboembolism in a Patient with a Gastrointestinal Stromal Tumor

Prospective Evaluation of FibroScan for the Diagnosis of Hepatic Fibrosis Compared with Liver Biopsy/AST Platelet Ratio Index and FIB-4 in Patients with Chronic HBV Infection

Small Bowel Cancers Diagnosed by Device-Assisted Enteroscopy at a U.S. Referral Center: A Five-Year Experience

Prognostic Factors and Survival Analysis of Antimitochondrial Antibody-Positive Primary Biliary Cirrhosis in Chinese Patients

Perinodal Adipose Tissue and Mesenteric Lymph Node Activation During Reactivated TNBS-Colitis in Rats

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials