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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Daisuke Uehara, Hiroki Tojima, Satoru Kakizaki, Yuichi Yamazaki, Norio Horiguchi, Daichi Takizawa, Ken Sato, Masanobu Yamada, Toshio Uraoka
• Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver (Dig Liver Dis) Vol. 51 Issue 2 Pg. 226-235 (02 2019) ISSN: 1878-3562 [Electronic] Netherlands
• PMID: 30442521 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Antigens, Differentiation
• Constitutive Androstane Receptor
• Gadd45b protein, mouse
• IL1B protein, mouse
• Interleukin-1beta
• Pregnane X Receptor
• Pyridines
• Receptors, Cytoplasmic and Nuclear
• Tumor Necrosis Factor-alpha
• Pregnenolone Carbonitrile
• 1,4-bis(2-(3,5-dichloropyridyloxy))benzene
• Dextran Sulfate

Topics

• Animals
• Antigens, Differentiation (metabolism)
• Apoptosis (drug effects)
• Colitis (drug therapy, etiology, immunology, metabolism)
• Constitutive Androstane Receptor
• Dextran Sulfate (pharmacology)
• Disease Models, Animal
• Inflammation (drug therapy, immunology)
• Interleukin-1beta (immunology)
• Mice
• Pregnane X Receptor (agonists, metabolism)
• Pregnenolone Carbonitrile (pharmacology)
• Pyridines (pharmacology)
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Tumor Necrosis Factor-alpha (immunology)