A mechanism for the anti-fibrogenic effects of the pregnane X receptor (PXR) in the liver: Inhibition of NF-κB?

Axon, Andrew; Cowie, David E.; Mann, Derek A.; Wright, Matthew C.

doi:10.1016/j.tox.2007.12.008

Cited by 11 publications

(6 citation statements)

References 51 publications

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“…Disruption of the molecular interaction between PXR and DNA through increased protein-protein interaction between the p65 subunit of NF-B and retinoid X receptor has been proposed as the molecular basis for transrepression of the xenobiotic response by inflammatory cytokines (Gu et al, 2006), although the precise mechanism that gives rise to the selective interaction between these two proteins is not currently known. Several studies indicate that PXR-mediated inhibition of NF-B is required for antifibrogenic effects and repression of CYP3A4 expression in hepatocytes (Axon et al, 2008;Yang et al, 2010). Further research will be necessary to elucidate the biochemical details of this response; however, the data presented here provide a stable platform for launching these important studies.…”

Section: Sumoylation Of Pxr 347mentioning

confidence: 89%

Pregnane X Receptor Is SUMOylated to Repress the Inflammatory Response

Xu²,

Staudinger³

2010

J Pharmacol Exp Ther

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Long-term treatment of patients with the macrolide antibiotic and prototypical activator of pregnane X receptor (PXR) rifampicin (Rif) inhibits the inflammatory response in liver. We show here that activation of the inflammatory response in hepatocytes strongly modulates SUMOylation of ligand-bound PXR. We provide evidence that the SUMOylated PXR contains SUMO3 chains, and feedback represses the immune response in hepatocytes. This information represents the first step in developing novel pharmaceutical strategies to treat inflammatory liver disease and prevent adverse drug reactions in patients experiencing acute or systemic inflammation. These studies also provide a molecular rationale for constructing a novel paradigm that uniquely defines the molecular basis of the interface between PXR-mediated gene activation, drug metabolism, and inflammation.

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Section: Sumoylation Of Pxr 347mentioning

confidence: 89%

Pregnane X Receptor Is SUMOylated to Repress the Inflammatory Response

Xu²,

Staudinger³

2010

J Pharmacol Exp Ther

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“…Consistent with this data, pxr −/− mice showed an increase in NF-κB target gene expression and demonstrated chronic inflammation in the small intestine 28 . In addition, PXR silencing increased expression of TNF-α, IL-8, and other proinflammatory cytokines, and decreased transforming growth factor β (TGF-β) and interferon-gamma-inducible 10 kD protein (IP-10) in primary fetal human colon epithelial cells 39 as well as human hepato 64 -or colon carcinoma cell lines 39–40 . Exposure to rifaximin caused a robust attenuation of inflammatory mediators and increased the generation of TGF-β 39 .…”

Section: Mechanisms For the Influence Of Pxr On Ibdmentioning

confidence: 99%

Pregnane X receptor as a target for treatment of inflammatory bowel disorders

Cheng

Shah

Gonzalez

2012

Trends in Pharmacological Sciences

146

125

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Pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, has a major role in the induction of genes involved in drug transport and metabolism. Recent studies in mice have provided insight into a novel function for PXR in inflammatory bowel disease (IBD). The mechanisms of the protective effect of PXR activation on IBD is not fully established, but is due in part to the attenuation of nuclear factor kappa B (NF-κB) signaling that results in lower expression of proinflammatory cytokines. Recent clinical trials with the antibiotic rifaximin, a PXR agonist in the gastrointestinal system, have revealed its potential therapeutic value in the treatment of intestinal inflammation in humans. Thus, PXR may be a novel target for IBD therapy.

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“…, 2006). One explanation of PXR's inhibitory effects on liver fibrosis could be PXR‐dependent inhibition of NF‐κB leading to reduced inflammation (Axon et al. , 2008).…”

Section: Pxr (Nr1i2) and Car (Nr1i3)mentioning

confidence: 99%

Nuclear receptors as therapeutic targets in cholestatic liver diseases

Zollner

Trauner

2008

British J Pharmacology

131

110

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Cholestasis results in intrahepatic accumulation of cytotoxic bile acids, which cause liver damage ultimately leading to biliary fibrosis and cirrhosis. Cholestatic liver injury is counteracted by a variety of adaptive hepatoprotective mechanisms including alterations in bile acid transport, synthesis and detoxification. The underlying molecular mechanisms are mediated mainly at a transcriptional level via a complex network involving nuclear receptors including the farnesoid X receptor, pregnane X receptor, vitamin D receptor and constitutive androstane receptor, which target overlapping, although not identical, sets of genes. Because the intrinsic adaptive response to bile acids cannot fully prevent liver injury in cholestasis, therapeutic targeting of these receptors via specific and potent agonists may further enhance the hepatic defence against toxic bile acids. Activation of these receptors results in repression of bile acid synthesis, induction of phases I and II bile acid hydroxylation and conjugation and stimulation of alternative bile acid export while limiting hepatocellular bile acid import. Furthermore, the use of nuclear receptor ligands may not only influence bile acid transport and metabolism but may also directly target hepatic fibrogenesis and inflammation. Many drugs already used to treat cholestasis and its complications such as pruritus (e.g. ursodeoxycholic acid, rifampicin, fibrates) may act via activation of nuclear receptors. More specific and potent nuclear receptor ligands are currently being developed. This article will review the current knowledge on nuclear receptors and their potential role in the treatment of cholestatic liver diseases.

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A mechanism for the anti-fibrogenic effects of the pregnane X receptor (PXR) in the liver: Inhibition of NF-κB?

Cited by 11 publications

References 51 publications

Pregnane X Receptor Is SUMOylated to Repress the Inflammatory Response

Pregnane X Receptor Is SUMOylated to Repress the Inflammatory Response

Pregnane X receptor as a target for treatment of inflammatory bowel disorders

Nuclear receptors as therapeutic targets in cholestatic liver diseases

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