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 2

RIF represses NF-κB–dependent transcription in an SXR-dependent manner.

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RIF represses NF-κB–dependent transcription in an SXR-dependent manner. ...
(A) RIF represses TPA- and TNF-α–induced NF-κB–dependent transcription in the presence of SXR. (B) Repression of NF-κB by RIF is not mediated by GR but by SXR. (C) Dose-dependent inhibition of NF-κB activity by RIF in the presence of SXR. HepG2 cells were cotransfected with an NF-κB–dependent reporter plasmid (NF-κBx3–LUC) and either indicated expression plasmid or control DNA. Cells were cotreated with TPA (0.1 μM) or TNF-α (10 ng/ml) in the absence or presence of RIF (10 μM) or DEX (0.1 nM). (D) SXR antagonizes the action of NF-κB on the COX-2 promoter. Cells were transfected with COX-2 promoter (COX-2–LUC) along with SXR expression vector or control vector. Transfected cells were treated with DMSO or RIF (10 μM) and 10 ng/ml TNF-α. (E) Dose-dependent inhibition of p65 activity by RIF in the presence of SXR. HepG2 cells were transfected with NF-κB reporter along with the indicated vectors. Cells were treated with TPA (0.1 nM) or RIF at the indicated concentrations 24 hours before the assay. (F) HepG2 cells were transfected with increasing amounts of SXR at 0.5:1, 1:1, or 2:1 ratios with p65 expression vector. The mutant form IκBα (IκBαM) vector was used at 1:1 ratio with p65 expression vector. HepG2 cells were cotransfected with NF-κB reporter, p65 expression vector, and either control DNA or SXR expression vector. Cells were treated with RIF at 10 μM for 24 hours as indicated before the assay.