Mutual repression between steroid and xenobiotic receptor and NF- B 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.

Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist

“…[31][32][33] Consistently, IL-1a treatment in WT-derived hepatocytes enhanced NF-kB activation and reciprocally attenuated the expression of CYP1A2, CYP2E1, and CYP3A11, whereas IL-1ra had little effect on NF-kB activation and subsequent expression of these enzymes (Figure 4). In spite of the absence of significant differences in intrahepatic IL-1a and …”

“…57,58 Activated NF-kB can form a heterodimer with RXR, thereby antagonizing PXR/SXR-mediated signaling. 33,59 These molecular mechanisms may account for downregulation of CYP genes by IL-1 [42][43][44][45] and suppressed CYP1A2, CYP2E1, and CYP3A11 expression observed in IL-1ra KO mice, which is presumed to exhibit enhanced IL-1-mediated signals.…”

Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

“…For example, our recent results suggest that PXR is important in preventing carcinogen-induced DNA damages (Naspinski et al, 2008). We and others have found cross talk between PXR-regulated pathway and NF-kB-regulated pathways (Gu et al, 2006;Zhou et al, 2006). These interactions create a 'checks and balances' relationship between pathways, which may have a role in some pathological processes such as IBD, which is a significant cancer risk factor.…”

“…These interactions create a 'checks and balances' relationship between pathways, which may have a role in some pathological processes such as IBD, which is a significant cancer risk factor. Indeed, it has been found that pxr-null mutant mice showed increased expression of NF-kB target genes and marked intestinal inflammation (Zhou et al, 2006) reminiscent of that seen in humans with inflammatory bowel diseases such as the celiac disease (Kagnoff, 2005). Consistent with this PXR-NF-kB mutual repressive cross talk, it has been observed that activation of PXR by the agonist pregnenolone-16a-carbonitrile (PCN) significantly reduced dextran sulphate sodium-induced IBD in mouse model (Shah et al, 2007).…”

The Aryl Hydrocarbon Receptor Complex and the Control of Gene Expression

“…Interestingly, induction of prostaglandin endoperoxide H synthase-2 by TCDD in rat hepatocytes appears to be mediated by both the AhR and by the ability of TCDD to increase overall C/EBP levels. 352 The ability of nuclear receptors and NFκB signaling to mutually repress transcription mediated by these factors has been firmly established [353][354][355] To gain insight into how the AhR and NFκB may interact at gene promoters, it is useful to examine the nature of the cross talk between nuclear receptors and NFκB. Numerous nuclear receptors have been shown to interact with RelA/p50, including, GR, ER, PPARγ, AR, and PXR.…”