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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Bibliographic Details
Published in:Digestive and liver disease 2019-02, Vol.51 (2), p.226-235
Main Authors: Uehara, Daisuke, Tojima, Hiroki, Kakizaki, Satoru, Yamazaki, Yuichi, Horiguchi, Norio, Takizawa, Daichi, Sato, Ken, Yamada, Masanobu, Uraoka, Toshio
Format: Article
Language:English
Subjects:
Animals
Antigens, Differentiation - metabolism
Apoptosis - drug effects
Colitis
Colitis - drug therapy
Colitis - etiology
Colitis - immunology
Colitis - metabolism
Constitutive androstane receptor
Dextran Sulfate - pharmacology
Dextran sulfate sodium
Disease Models, Animal
Inflammation - drug therapy
Inflammation - immunology
Inflammatory bowel disease
Interleukin-1beta - immunology
Mice
Nuclear receptor
Pregnane X receptor
Pregnane X Receptor - agonists
Pregnane X Receptor - metabolism
Pregnenolone Carbonitrile - pharmacology
Pyridines - pharmacology
Receptors, Cytoplasmic and Nuclear - metabolism
Tumor Necrosis Factor-alpha - immunology
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Summary: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.
ISSN:1590-8658
1878-3562
DOI:10.1016/j.dld.2018.10.008