Role of the xenobiotic receptor in inflammatory bowel disease

Razvan Arsenescu, Violeta Arsenescu, Jian Zhong, Munira Nasser, Razvan Melinte, R. W.Cameron Dingle, Hollie Swanson, Willem J. De Villiers

Research output: Contribution to journalArticle

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Abstract

Background: Gene-environment interplay modulates inflammatory bowel diseases (IBD). Dioxin-like compounds can activate the aryl hydrocarbon receptor (AhR) and alter macrophage function as well as T-cell polarization. We hypothesized that attenuation of the AhR signaling pathway will ameliorate colitis in a murine model of IBD. Methods: Dextran sulfate sodium (DSS) colitis was induced in C57BL/6 AhR null mice (AhR-/-), heterozygous mice (AhR-/+), and their wildtype (WT) littermates. Clinical and morphopathological parameters were used to compare the groups. Patients: AhR pathway activation was analyzed in biopsy specimens from 25 IBD patients and 15 healthy controls. Results: AhR-/- mice died before the end of the treatment. However, AhR-/+ mice exhibited decreased disease activity compared to WT mice. The AhR-/+ mice expressed less proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) (6.1- versus 15.7-fold increase) and IL17 (23.7- versus 67.9-fold increase) and increased antiinflammatory IL-10 (2.3-fold increase) compared with the AhR+/+ mice in the colon. Colonic macrophage infiltration was attenuated in the AhR-/+ group. AhR and its downstream targets were significantly upregulated in IBD patients versus control (CYP1A1 -19.9, and IL8- 10-fold increase). Conclusions: Attenuation of the AhR receptor expression resulted in a protective effect during DSS-induced colitis, while the absence of AhR exacerbated the disease. Abnormal AhR pathway activation in the intestinal mucosa of IBD patients may promote chronic inflammation. Modulation of AhR signaling pathway via the diet, cessation of smoking, or administration of AhR antagonists could be viable strategies for the treatment of IBD. (Inflamm Bowel Dis 2010;)

Original languageEnglish (US)
Pages (from-to)1149-1162
Number of pages14
JournalInflammatory bowel diseases
Volume17
Issue number5
DOIs
StatePublished - May 1 2011
Externally publishedYes

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Aryl Hydrocarbon Receptors
Xenobiotics
Inflammatory Bowel Diseases
Colitis
Dextran Sulfate
Macrophages
Cytochrome P-450 CYP1A1
Dioxins
Smoking Cessation
Intestinal Mucosa
Interleukin-8
Interleukin-10
Mouse Ahr protein
Colon
Anti-Inflammatory Agents
Tumor Necrosis Factor-alpha

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Gastroenterology

Cite this

Arsenescu, R., Arsenescu, V., Zhong, J., Nasser, M., Melinte, R., Dingle, R. W. C., ... De Villiers, W. J. (2011). Role of the xenobiotic receptor in inflammatory bowel disease. Inflammatory bowel diseases, 17(5), 1149-1162. https://doi.org/10.1002/ibd.21463
Arsenescu, Razvan ; Arsenescu, Violeta ; Zhong, Jian ; Nasser, Munira ; Melinte, Razvan ; Dingle, R. W.Cameron ; Swanson, Hollie ; De Villiers, Willem J. / Role of the xenobiotic receptor in inflammatory bowel disease. In: Inflammatory bowel diseases. 2011 ; Vol. 17, No. 5. pp. 1149-1162.
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Arsenescu, R, Arsenescu, V, Zhong, J, Nasser, M, Melinte, R, Dingle, RWC, Swanson, H & De Villiers, WJ 2011, 'Role of the xenobiotic receptor in inflammatory bowel disease', Inflammatory bowel diseases, vol. 17, no. 5, pp. 1149-1162. https://doi.org/10.1002/ibd.21463

Role of the xenobiotic receptor in inflammatory bowel disease. / Arsenescu, Razvan; Arsenescu, Violeta; Zhong, Jian; Nasser, Munira; Melinte, Razvan; Dingle, R. W.Cameron; Swanson, Hollie; De Villiers, Willem J.

In: Inflammatory bowel diseases, Vol. 17, No. 5, 01.05.2011, p. 1149-1162.

Research output: Contribution to journalArticle

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T1 - Role of the xenobiotic receptor in inflammatory bowel disease

AU - Arsenescu, Razvan

AU - Arsenescu, Violeta

AU - Zhong, Jian

AU - Nasser, Munira

AU - Melinte, Razvan

AU - Dingle, R. W.Cameron

AU - Swanson, Hollie

AU - De Villiers, Willem J.

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N2 - Background: Gene-environment interplay modulates inflammatory bowel diseases (IBD). Dioxin-like compounds can activate the aryl hydrocarbon receptor (AhR) and alter macrophage function as well as T-cell polarization. We hypothesized that attenuation of the AhR signaling pathway will ameliorate colitis in a murine model of IBD. Methods: Dextran sulfate sodium (DSS) colitis was induced in C57BL/6 AhR null mice (AhR-/-), heterozygous mice (AhR-/+), and their wildtype (WT) littermates. Clinical and morphopathological parameters were used to compare the groups. Patients: AhR pathway activation was analyzed in biopsy specimens from 25 IBD patients and 15 healthy controls. Results: AhR-/- mice died before the end of the treatment. However, AhR-/+ mice exhibited decreased disease activity compared to WT mice. The AhR-/+ mice expressed less proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) (6.1- versus 15.7-fold increase) and IL17 (23.7- versus 67.9-fold increase) and increased antiinflammatory IL-10 (2.3-fold increase) compared with the AhR+/+ mice in the colon. Colonic macrophage infiltration was attenuated in the AhR-/+ group. AhR and its downstream targets were significantly upregulated in IBD patients versus control (CYP1A1 -19.9, and IL8- 10-fold increase). Conclusions: Attenuation of the AhR receptor expression resulted in a protective effect during DSS-induced colitis, while the absence of AhR exacerbated the disease. Abnormal AhR pathway activation in the intestinal mucosa of IBD patients may promote chronic inflammation. Modulation of AhR signaling pathway via the diet, cessation of smoking, or administration of AhR antagonists could be viable strategies for the treatment of IBD. (Inflamm Bowel Dis 2010;)

AB - Background: Gene-environment interplay modulates inflammatory bowel diseases (IBD). Dioxin-like compounds can activate the aryl hydrocarbon receptor (AhR) and alter macrophage function as well as T-cell polarization. We hypothesized that attenuation of the AhR signaling pathway will ameliorate colitis in a murine model of IBD. Methods: Dextran sulfate sodium (DSS) colitis was induced in C57BL/6 AhR null mice (AhR-/-), heterozygous mice (AhR-/+), and their wildtype (WT) littermates. Clinical and morphopathological parameters were used to compare the groups. Patients: AhR pathway activation was analyzed in biopsy specimens from 25 IBD patients and 15 healthy controls. Results: AhR-/- mice died before the end of the treatment. However, AhR-/+ mice exhibited decreased disease activity compared to WT mice. The AhR-/+ mice expressed less proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) (6.1- versus 15.7-fold increase) and IL17 (23.7- versus 67.9-fold increase) and increased antiinflammatory IL-10 (2.3-fold increase) compared with the AhR+/+ mice in the colon. Colonic macrophage infiltration was attenuated in the AhR-/+ group. AhR and its downstream targets were significantly upregulated in IBD patients versus control (CYP1A1 -19.9, and IL8- 10-fold increase). Conclusions: Attenuation of the AhR receptor expression resulted in a protective effect during DSS-induced colitis, while the absence of AhR exacerbated the disease. Abnormal AhR pathway activation in the intestinal mucosa of IBD patients may promote chronic inflammation. Modulation of AhR signaling pathway via the diet, cessation of smoking, or administration of AhR antagonists could be viable strategies for the treatment of IBD. (Inflamm Bowel Dis 2010;)

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Arsenescu R, Arsenescu V, Zhong J, Nasser M, Melinte R, Dingle RWC et al. Role of the xenobiotic receptor in inflammatory bowel disease. Inflammatory bowel diseases. 2011 May 1;17(5):1149-1162. https://doi.org/10.1002/ibd.21463