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

Uehara, Daisuke; Tojima, Hiroki; Kakizaki, Satoru; Yamazaki, Yuichi; Horiguchi, Norio; Takizawa, Daichi; Sato, Ken; Yamada, Masanobu; Uraoka, Toshio

doi:10.1016/j.dld.2018.10.008

Cited by 13 publications

(9 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2). 153 Like PXR, CAR is thought to regulate IEC function in the context of wound healing; the selective human CAR agonist 6-(4-chlorophenyl)imidazo[2,1-b] [1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO) 154 increases IEC migratory activity. 152 In addition, a series of recent studies suggest that CAR-dependent transcriptional activity in IECs is influenced by the enteric flora.…”

Section: Farsenoid X Receptormentioning

confidence: 99%

Emerging roles of bile acids in mucosal immunity and inflammation

2019

View full text Add to dashboard Cite

Bile acids are cholesterol-derived surfactants that circulate actively between the liver and ileum and that are classically recognized for emulsifying dietary lipids to facilitate absorption. More recent studies, however, have revealed new functions of bile acids; as pleotropic signaling metabolites that regulate diverse metabolic and inflammatory pathways in multiple cell types and tissues through dynamic interactions with both germline-encoded host receptors and the microbiota. Accordingly, perturbed bile acid circulation and/or metabolism is now implicated in the pathogenesis of cholestatic liver diseases, metabolic syndrome, colon cancer, and inflammatory bowel diseases (IBDs). Here, we discuss the three-dimensional interplay between bile acids, the microbiota, and the mucosal immune system, focusing on the mechanisms that regulate intestinal homeostasis and inflammation. Although the functions of bile acids in mucosal immune regulation are only beginning to be appreciated, targeting bile acids and their cellular receptors has already proven an important area of new drug discovery.

show abstract

Section: Farsenoid X Receptormentioning

confidence: 99%

Emerging roles of bile acids in mucosal immunity and inflammation

2019

View full text Add to dashboard Cite

show abstract

“…In the pre-clinical DSS mouse model, especially wound healing of intestinal epithelial cells is reduced in Car -deficient mice whereas activation of CAR using a selective CAR agonist 3,3',5,5'-tetrachloro-1,4-bis(pyridyloxy)benzene (TCPOBOP) enhances mucosal healing (67) in mice (Figure 2). In a rat DSS colitis model, CAR agonists reduced the mRNA expression of several pro-inflammatory cytokines in a CAR-dependent manner; CAR inhibited apoptosis by inducing Gadd45b within an in vitro cell analysis (124). Therefore, CAR activation may also prove effective in patients with IBD.…”

Section: Introductionmentioning

confidence: 99%

“…PXR agonists reduce the mRNA expression of several pro-inflammatory cytokines in a PXR-dependent manner such as TNF-α and IL-1β in a rat DSS colitis model (124). PXR has been implicated in the pathogenesis of IBD, and its activator rifaximin (works only in humans, not in mice) has demonstrated efficacy in CD and UC (Table 2B).…”

Section: Introductionmentioning

confidence: 99%

Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD

et al. 2019

View full text Add to dashboard Cite

Gastrointestinal (GI) homeostasis is strongly dependent on nuclear receptor (NR) functions. They play a variety of roles ranging from nutrient uptake, sensing of microbial metabolites, regulation of epithelial intestinal cell integrity to shaping of the intestinal immune cell repertoire. Several NRs are associated with GI pathologies; therefore, systematic analysis of NR biology, the underlying molecular mechanisms, and regulation of target genes can be expected to help greatly in uncovering the course of GI diseases. Recently, an increasing number of NRs has been validated as potential drug targets for therapeutic intervention in patients with inflammatory bowel disease (IBD). Besides the classical glucocorticoids, especially PPARγ, VDR, or PXR-selective ligands are currently being tested with promising results in clinical IBD trials. Also, several pre-clinical animal studies are being performed with NRs. This review focuses on the complex biology of NRs and their context-dependent anti- or pro-inflammatory activities in the regulation of gastrointestinal barrier with special attention to NRs already pharmacologically targeted in clinic and pre-clinical IBD treatment regimens.

show abstract

“…CAR activation has been reported to reduce inflammatory response in several pathologic conditions. In this way, CAR protected against experimental colitis by inhibiting proinflammatory cytokines [31]. In that study, Uehara et al showed that NF-κB target genes such as IL-1β and chemokine receptor CCR2 were markedly down-regulated by CAR agonism [31].…”

Section: Discussionmentioning

confidence: 96%

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium

López-Riera

Ortega

Hueso

et al. 2021

IJMS

View full text Add to dashboard Cite

Leukocyte cell recruitment into the vascular subendothelium constitutes an early event in the atherogenic process. As the effect of the constitutive androstane receptor (CAR) on leukocyte recruitment and endothelial dysfunction is poorly understood, this study investigated whether the role of CAR activation can affect this response and the underlying mechanisms involved. Under physiological flow conditions, TNFα-induced endothelial adhesion of human leukocyte cells was concentration-dependently inhibited by preincubation of human umbilical arterial endothelial cells with the selective human CAR ligand CITCO. CAR agonism also prevented TNFα induced VCAM-1 expression, as well as MCP-1/CCL-2 and RANTES/CCL-5 release in endothelial cells. Suppression of CAR expression with a small interfering RNA abrogated the inhibitory effects of CITCO on these responses. Furthermore, CITCO increased interaction of CAR with Retinoid X Receptor (RXR) and reduced TNFα-induced p38-MAPK/NF-κB activation. In vivo, using intravital microscopy in the mouse cremasteric microcirculation treatment with the selective mouse CAR ligand TCPOBOP inhibited TNFα-induced leukocyte rolling flux, adhesion, and emigration and decreased VCAM-1 in endothelium. These results reveal that CAR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps in the leukocyte recruitment cascade. Therefore, CAR agonists may constitute a new therapeutic tool in controlling cardiovascular disease-associated inflammatory processes.

show abstract

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

Cited by 13 publications

References 30 publications

Emerging roles of bile acids in mucosal immunity and inflammation

Emerging roles of bile acids in mucosal immunity and inflammation

Nuclear Receptors Regulate Intestinal Inflammation in the Context of IBD

Activation of the Constitutive Androstane Receptor Inhibits Leukocyte Adhesiveness to Dysfunctional Endothelium

Contact Info

Product

Resources

About