Further evidence that PXR activators protect against colitis

[Guest guest]

Dear All;

Recently there has been interest in a nuclear receptor called the

pregnane X receptor (PXR) (also known as the steroid and xenobiotic

receptor, SXR) in both IBD and PSC. PXR controls the expression of a

number of genes encoding enzymes of bile metabolism and transport,

and so plays a key role in the liver in detoxification of bile acids

and xenobiotics. PXR is down-regulated in IBD in the gut, and so this

also impairs detoxification in the gut. Polymorphisms/variants in the

PXR gene have been found to be associated with IBD in the Irish

population, and are associated with severity of PSC in the

Scandinavian population. It's been shown that a key inflammatory

molecule, nuclear factor kappa B (NFkB), that is elevated in IBD

causes a down-regulation of PXR. This may contribute to cholestasis

and liver injury through build-up of toxic bile acids in the liver.

PXR activation on the other hand, down-regulates NFkB. So PXR appears

to be able to counteract NFkB-mediated inflammation. A drug that

activates PXR is rifampin, which is used to control pruritus in PSC

and other cholestatic liver diseases.

It's now been shown that in mice deficient in PXR, the PXR activator,

pregnenolone-16alpha-carbonitrile, is not able to protect against the

development of colitis. In normal mice, however, activation of PXR

with pregnenolone-16alpha-carbonitrile suppresses inflammation by

repressing NFkB:

Am J Physiol Gastrointest Liver Physiol. 2006 Dec 14; [Epub ahead of

print]

Pregnane X Receptor Activation Ameliorates DSS-Induced IBD Via

Inhibition of NF{kappa}B Target Gene Expression.

Shah Y, Ma X, Morimura K, Kim I, FJ

Laboratory of Metabolism, National Cancer Institute, Bethesda,

land, United States.

Objectives: Pregnane X receptor expression (PXR) has been shown to be

protective in inflammatory bowel disease (IBD) in humans. However,

the mechanism by which PXR provides protection remains unclear.

Methods: Wild-type and Pxr-null mice were treated with the PXR

agonist, pregnenolone-16alpha-carbonitrile or vehicle and

administered 2.5% dextran sulfate sodium (DSS) in drinking water to

induce IBD. Typical clinical symptoms were evaluated on a daily

basis. In vivo intestinal permeability assay and proinflammatory

cytokine analysis were performed. Results: PXR agonist-treated mice

were protected from DSS-induced colitis in comparison to vehicle-

treated mice, as defined by body weight loss, diarrhea, rectal

bleeding, colon length and histology. Pregnenolone-16alpha-

carbonitrile did not decrease the severity of IBD in Pxr-null mice.

PXR agonist treatment did not increase epithelial barrier function,

but did decrease mRNA expression of several NFkappaB target genes in

a PXR-dependent manner. Conclusions: The present study clearly

demonstrates a protective role for PXR agonist in DSS-induced IBD.

The data suggest that PXR-mediated repression of NFkappaB target

genes in the colon is the mechanism by which PXR activation decreases

susceptibility of mice to DSS-induced IBD. Key words: pregnane X

receptor, inflammatory bowel disease, NFkappaB, dextran sulfate

sodium. PMID: 17170021.

Best regards,

Dave

(father of (21); PSC 07/03; UC 08/03)