Constitutive androstane receptor and pregnane X receptor cooperatively ameliorate DSS-induced colitis
Nuclear receptor pregnane X receptor (PXR) was shown to be protective in case of dextran sulfate sodium (DSS)-induced colitis. Constitutive androstane receptor (CAR) belongs to the same nuclear receptor subfamily with PXR. The roles of both receptors in DSS-induced colitis were evaluated. Wild-type,...
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| Published in | Digestive and liver disease Vol. 51; no. 2; pp. 226 - 235 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
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Netherlands
Elsevier Ltd
01.02.2019
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| ISSN | 1590-8658 1878-3562 1878-3562 |
| DOI | 10.1016/j.dld.2018.10.008 |
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| Abstract | Nuclear receptor pregnane X receptor (PXR) was shown to be protective in case of dextran sulfate sodium (DSS)-induced colitis. Constitutive androstane receptor (CAR) belongs to the same nuclear receptor subfamily with PXR. The roles of both receptors in DSS-induced colitis were evaluated.
Wild-type, Car-null, Pxr-null, and Car/Pxr-null mice were treated with a CAR/PXR agonist or vehicle and administered 2.5% DSS in the drinking water. The typical clinical symptoms, histological scoring, proinflammatory cytokine, and apoptosis were analyzed.
Mice treated with the PXR agonist pregnenolone-16α-carbonitrile (PCN) were protected from DSS-induced colitis, as in a previous study. Mice treated with the CAR agonist, 4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) were also protected from DSS-induced colitis. Interestingly, the protective effects of PCN in the Car-null mice and those of TCPOBOP in the Pxr-null mice both decreased. PCN or TCPOBOP pretreatment significantly decreased the macrophage and monocyte infiltration in DSS-induced colitis. PXR and CAR agonists reduced the mRNA expression of several proinflammatory cytokines in a PXR- and CAR-dependent manner, respectively. CAR inhibited apoptosis by inducing Gadd45b. PXR inhibited TNF-α and IL-1b and CAR induced Gadd45b in in vitro cell analyses.
We showed that CAR and PXR cooperatively ameliorate DSS-induced colitis. PXR and CAR protected against DSS-induced colitis by inhibiting proinflammatory cytokines and apoptosis, respectively. |
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| AbstractList | Nuclear receptor pregnane X receptor (PXR) was shown to be protective in case of dextran sulfate sodium (DSS)-induced colitis. Constitutive androstane receptor (CAR) belongs to the same nuclear receptor subfamily with PXR. The roles of both receptors in DSS-induced colitis were evaluated.
Wild-type, Car-null, Pxr-null, and Car/Pxr-null mice were treated with a CAR/PXR agonist or vehicle and administered 2.5% DSS in the drinking water. The typical clinical symptoms, histological scoring, proinflammatory cytokine, and apoptosis were analyzed.
Mice treated with the PXR agonist pregnenolone-16α-carbonitrile (PCN) were protected from DSS-induced colitis, as in a previous study. Mice treated with the CAR agonist, 4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) were also protected from DSS-induced colitis. Interestingly, the protective effects of PCN in the Car-null mice and those of TCPOBOP in the Pxr-null mice both decreased. PCN or TCPOBOP pretreatment significantly decreased the macrophage and monocyte infiltration in DSS-induced colitis. PXR and CAR agonists reduced the mRNA expression of several proinflammatory cytokines in a PXR- and CAR-dependent manner, respectively. CAR inhibited apoptosis by inducing Gadd45b. PXR inhibited TNF-α and IL-1b and CAR induced Gadd45b in in vitro cell analyses.
We showed that CAR and PXR cooperatively ameliorate DSS-induced colitis. PXR and CAR protected against DSS-induced colitis by inhibiting proinflammatory cytokines and apoptosis, respectively. Nuclear receptor pregnane X receptor (PXR) was shown to be protective in case of dextran sulfate sodium (DSS)-induced colitis. Constitutive androstane receptor (CAR) belongs to the same nuclear receptor subfamily with PXR. The roles of both receptors in DSS-induced colitis were evaluated.BACKGROUNDNuclear receptor pregnane X receptor (PXR) was shown to be protective in case of dextran sulfate sodium (DSS)-induced colitis. Constitutive androstane receptor (CAR) belongs to the same nuclear receptor subfamily with PXR. The roles of both receptors in DSS-induced colitis were evaluated.Wild-type, Car-null, Pxr-null, and Car/Pxr-null mice were treated with a CAR/PXR agonist or vehicle and administered 2.5% DSS in the drinking water. The typical clinical symptoms, histological scoring, proinflammatory cytokine, and apoptosis were analyzed.METHODSWild-type, Car-null, Pxr-null, and Car/Pxr-null mice were treated with a CAR/PXR agonist or vehicle and administered 2.5% DSS in the drinking water. The typical clinical symptoms, histological scoring, proinflammatory cytokine, and apoptosis were analyzed.Mice treated with the PXR agonist pregnenolone-16α-carbonitrile (PCN) were protected from DSS-induced colitis, as in a previous study. Mice treated with the CAR agonist, 4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) were also protected from DSS-induced colitis. Interestingly, the protective effects of PCN in the Car-null mice and those of TCPOBOP in the Pxr-null mice both decreased. PCN or TCPOBOP pretreatment significantly decreased the macrophage and monocyte infiltration in DSS-induced colitis. PXR and CAR agonists reduced the mRNA expression of several proinflammatory cytokines in a PXR- and CAR-dependent manner, respectively. CAR inhibited apoptosis by inducing Gadd45b. PXR inhibited TNF-α and IL-1b and CAR induced Gadd45b in in vitro cell analyses.RESULTSMice treated with the PXR agonist pregnenolone-16α-carbonitrile (PCN) were protected from DSS-induced colitis, as in a previous study. Mice treated with the CAR agonist, 4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) were also protected from DSS-induced colitis. Interestingly, the protective effects of PCN in the Car-null mice and those of TCPOBOP in the Pxr-null mice both decreased. PCN or TCPOBOP pretreatment significantly decreased the macrophage and monocyte infiltration in DSS-induced colitis. PXR and CAR agonists reduced the mRNA expression of several proinflammatory cytokines in a PXR- and CAR-dependent manner, respectively. CAR inhibited apoptosis by inducing Gadd45b. PXR inhibited TNF-α and IL-1b and CAR induced Gadd45b in in vitro cell analyses.We showed that CAR and PXR cooperatively ameliorate DSS-induced colitis. PXR and CAR protected against DSS-induced colitis by inhibiting proinflammatory cytokines and apoptosis, respectively.CONCLUSIONSWe showed that CAR and PXR cooperatively ameliorate DSS-induced colitis. PXR and CAR protected against DSS-induced colitis by inhibiting proinflammatory cytokines and apoptosis, respectively. |
| Author | Uraoka, Toshio Yamazaki, Yuichi Tojima, Hiroki Yamada, Masanobu Kakizaki, Satoru Takizawa, Daichi Uehara, Daisuke Horiguchi, Norio Sato, Ken |
| Author_xml | – sequence: 1 givenname: Daisuke surname: Uehara fullname: Uehara, Daisuke organization: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan – sequence: 2 givenname: Hiroki surname: Tojima fullname: Tojima, Hiroki organization: Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan – sequence: 3 givenname: Satoru orcidid: 0000-0002-1508-584X surname: Kakizaki fullname: Kakizaki, Satoru email: kakizaki@gunma-u.ac.jp organization: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan – sequence: 4 givenname: Yuichi surname: Yamazaki fullname: Yamazaki, Yuichi organization: Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan – sequence: 5 givenname: Norio surname: Horiguchi fullname: Horiguchi, Norio organization: Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan – sequence: 6 givenname: Daichi surname: Takizawa fullname: Takizawa, Daichi organization: Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan – sequence: 7 givenname: Ken surname: Sato fullname: Sato, Ken organization: Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan – sequence: 8 givenname: Masanobu surname: Yamada fullname: Yamada, Masanobu organization: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan – sequence: 9 givenname: Toshio surname: Uraoka fullname: Uraoka, Toshio organization: Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan |
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| Keywords | Inflammatory bowel disease Nuclear receptor Colitis Constitutive androstane receptor Pregnane X receptor Dextran sulfate sodium |
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| SubjectTerms | Colitis Constitutive androstane receptor Dextran sulfate sodium Inflammatory bowel disease Nuclear receptor Pregnane X receptor |
| Title | Constitutive androstane receptor and pregnane X receptor cooperatively ameliorate DSS-induced colitis |
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