The PXR is a drug target for chronic inflammatory liver disease.
PXR activators are used to treat pruritus in chronic inflammatory liver diseases such as primary biliary cirrhosis (PBC). The aims of this study were to determine whether PXR activators could have an additional benefit of inhibiting inflammation in the liver, and determine whether cyclosporin A - which more effectively prevents PBC recurrence in transplanted patients than FK506 - is a PXR activator. In SJL/J mice (which have constitutively high levels of hepatic portal tract inflammatory cell recruitment), feeding a PXR activator inhibited inflammation, TNFalpha and Il-1alpha mRNA expression in SJL/J-PXR(+/+), but not SJL/J-PXR(-/-). Monocytic cells - a major source of inflammatory mediators such as TNFalpha - expressed the PXR and PXR activators inhibited endotoxin-induced NF-kappaB activation and TNFalpha expression. PXR activation also inhibited endotoxin-stimulated TNFalpha secretion from liver monocytes/macrophages isolated from PXR(+/+) mice, but not from cells isolated from PXR(-/-) mice. To confirm that PXR activation inhibits NF-kappaB in vivo, 3x-kappaB-luc fibrotic mice (which express a luciferase gene regulated by NF-kappaB) were imaged after treatment with the hepatotoxin CCl(4). PXR activator inhibited the induction of hepatic NF-kappaB activity without affecting CCl(4) toxicity/hepatic damage. Using a PXR reporter gene assay, cyclosporin A - but not FK506 - was shown to be a direct PXR activator, and also to induce expression of the classic PXR-regulated CYP3A4 gene in human hepatocytes and in a cell line null for the FXR, a nuclear receptor with similar properties to the PXR.


CONCLUSIONS
PXR activation is anti-inflammatory in the liver and the effects of cyclosporin A in PBC disease recurrence may be mediated in part via the PXR. Since PXR activation promotes hepatocyte growth and is also anti-fibrogenic, the PXR may be an excellent drug target for the treatment of chronic inflammatory liver disease.
Wallace
Karen
K
Institute of Cellular Medicine, University of Newcastle, Upon Tyne, UK.
Cowie
David E
DE
Konstantinou
Dimitrios K
DK
Hill
Stephen J
SJ
Tjelle
Torunn E
TE
Axon
Andrew
A
Koruth
Matthew
M
White
Steven A
SA
Carlsen
Harald
H
Mann
Derek A
DA
Wright
Matthew C
MC
D000818:Animals; D002460:Cell Line; D016572:Cyclosporine / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation; D006521:Hepatitis, Chronic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine