Constitutive androstane receptor and pregnane X receptor cooperatively ameliorate DSS-induced colitis

• Published in: Digestive and liver disease Vol. 51; no. 2; pp. 226 - 235
• Main Authors: Uehara, Daisuke, Tojima, Hiroki, Kakizaki, Satoru, Yamazaki, Yuichi, Horiguchi, Norio, Takizawa, Daichi, Sato, Ken, Yamada, Masanobu, Uraoka, Toshio
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.02.2019
• Subjects: Colitis; Constitutive androstane receptor; Dextran sulfate sodium; Inflammatory bowel disease; Nuclear receptor; Pregnane X receptor; Inflammatory bowel disease; Nuclear receptor; Colitis; Constitutive androstane receptor; Pregnane X receptor; Dextran sulfate sodium
• ISSN: 1590-8658; 1878-3562; 1878-3562
• DOI: 10.1016/j.dld.2018.10.008

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.