Mutual repression between steroid and xenobiotic receptor and NF-κB signaling pathways links xenobiotic metabolism and inflammation
Changcheng Zhou, Michelle M. Tabb, Edward L. Nelson, Felix Grün, Suman Verma, Asal Sadatrafiei, Min Lin, Shyamali Mallick, Barry M. Forman, Kenneth E. Thummel, Bruce Blumberg
Changcheng Zhou, Michelle M. Tabb, Edward L. Nelson, Felix Grün, Suman Verma, Asal Sadatrafiei, Min Lin, Shyamali Mallick, Barry M. Forman, Kenneth E. Thummel, Bruce Blumberg
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Research Article Immunology

Mutual repression between steroid and xenobiotic receptor and NF-κB signaling pathways links xenobiotic metabolism and inflammation

Abstract

While it has long been known that inflammation and infection reduce expression of hepatic cytochrome P450 (CYP) genes involved in xenobiotic metabolism and that exposure to xenobiotic chemicals can impair immune function, the molecular mechanisms underlying both of these phenomena have remained largely unknown. Here we show that activation of the nuclear steroid and xenobiotic receptor (SXR) by commonly used drugs in humans inhibits the activity of NF-κB, a key regulator of inflammation and the immune response. NF-κB target genes are upregulated and small bowel inflammation is significantly increased in mice lacking the SXR ortholog pregnane X receptor (PXR), thereby demonstrating a direct link between SXR and drug-mediated antagonism of NF-κB. Interestingly, NF-κB activation reciprocally inhibits SXR and its target genes whereas inhibition of NF-κB enhances SXR activity. This SXR/PXR–NF-κB axis provides a molecular explanation for the suppression of hepatic CYP mRNAs by inflammatory stimuli as well as the immunosuppressant effects of xenobiotics and SXR-responsive drugs. This mechanistic relationship has clinical consequences for individuals undergoing therapeutic exposure to the wide variety of drugs that are also SXR agonists.

Authors

Changcheng Zhou, Michelle M. Tabb, Edward L. Nelson, Felix Grün, Suman Verma, Asal Sadatrafiei, Min Lin, Shyamali Mallick, Barry M. Forman, Kenneth E. Thummel, Bruce Blumberg

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Figure 4

PCN inhibits TNF-α–induced NF-κB target gene expression in WT primary hepatocytes but not in PXR knockout primary hepatocytes.

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PCN inhibits TNF-α–induced NF-κB target gene expression in WT primary he...
(A) Mouse primary hepatocytes were isolated from WT or PXR knockout mice. Total RNAs were isolated and expression of NF-κB target genes was determined by QRT-PCR. (B and C) Mouse primary hepatocytes were pretreated for 18 hours with 10 μM PCN before the addition of 10 ng/ml mouse TNF-α and incubation for 3 hours. Total RNAs were isolated and expression of NF-κB target genes, IκBα (B), and TNF-α (C) was determined by QRT-PCR. n = 3. **P < 0.01; #P < 0.001.