Xenobiotic receptor meets NF-κB, a collision in the small bowel
Authors: Wen Xie, Yanan Tian
Journal: Cell Metabolism (2006)

It has long been appreciated that inflammation and infection reduce drug metabolism and that exposure to drug metabolism-inducing xenobiotics can impair immune function. A new study reveals the mutual repression between the xenobiotic nuclear receptor PXR/SXR and NF-κB signaling pathways, providing a molecular mechanism linking xenobiotic metabolism and inflammation (Zhou et al., 2006Zhou C. Tabb M.M. Nelson E.L. Grun F. Verma S. Sadatrafiei A. Lin M. Mallick S. Forman B.M. Thummel K.E. Blumberg B. J. Clin. Invest. 2006; 116: 2280-2289Crossref PubMed Scopus (299) Google Scholar). It has long been appreciated that inflammation and infection reduce drug metabolism and that exposure to drug metabolism-inducing xenobiotics can impair immune function. A new study reveals the mutual repression between the xenobiotic nuclear receptor PXR/SXR and NF-κB signaling pathways, providing a molecular mechanism linking xenobiotic metabolism and inflammation (Zhou et al., 2006Zhou C. Tabb M.M. Nelson E.L. Grun F. Verma S. Sadatrafiei A. Lin M. Mallick S. Forman B.M. Thummel K.E. Blumberg B. J. Clin. Invest. 2006; 116: 2280-2289Crossref PubMed Scopus (299) Google Scholar). Gene and environment interactions are a vital force that constantly shape living organisms. In dealing with xenobiotics, mammals have evolved a defensive network governed by the so-called xenobiotic receptors/xeno-senors, such as pregnane X receptor (PXR, also known as steroid and xenobiotic receptor or SXR) and constitutive androstane receptor (CAR). When encountering infectious agents, organisms have enlisted the innate and adaptive immune defensive systems, in which the nuclear factor kappa B (NF-κB) plays an essential regulatory role. Armed with the chemical and immunological defensive systems, mammals by and large cope well with the challenge of noxious substances or infectious agents that have been part of their life. However, these two defensive systems do not always run in sync; in some cases one prevails at the cost of the other. It has been known in the clinic that inflammation and infection reduce hepatointestinal drug metabolism capacity (Aitken et al., 2006Aitken A.E. Richardson T.A. Morgan E.T. Annu. Rev. Pharmacol. Toxicol. 2006; 46: 123-149Crossref PubMed Scopus (330) Google Scholar). Meanwhile, drug metabolism-inducing xenobiotics/drugs, such as the antibiotic rifampicin, are known to repress the immune system (Paunescu, 1970Paunescu E. Nature. 1970; 228: 1188-1190Crossref PubMed Scopus (83) Google Scholar). In the July issue of the Journal of Clinical Investigation, Zhou et al. demonstrated mutual suppression between PXR/SXR and NF-κB, providing a potential molecular mechanism that links xenobiotic metabolism and inflammation (Zhou et al., 2006Zhou C. Tabb M.M. Nelson E.L. Grun F. Verma S. Sadatrafiei A. Lin M. Mallick S. Forman B.M. Thummel K.E. Blumberg B. J. Clin. Invest. 2006; 116: 2280-2289Crossref PubMed Scopus (299) Google Scholar). PXR/SXR was isolated as an orphan nuclear receptor that regulates the metabolism and disposition of various xenobiotics and endobiotics. The xeno-sensor function of PXR is achieved through its coordinated transcriptional regulation of Phase I and Phase II drug metabolizing enzymes as well as the "Phase III" drug transporters (Xie et al., 2004Xie W. Uppal H. Saini S.P. Mu Y. Little J.M. Radominska-Pandya A. Zemaitis M.A. Drug Discov. Today. 2004; 9: 442-449Crossref PubMed Scopus (106) Google Scholar). The flexibility in its ligand binding pocket enables PXR/SXR to function as a xenobiotic receptor through interacting with a wide range of structurally diverse compounds. Xeno- and endobiotics that activate PXR/SXR include various prescription drugs, herbal medicines, environmental toxicants, and bile acids. Zhou and colleagues demonstrated that drugs that typically activate human PXR/SXR, such as rifampicin, suppressed the expression of typical NF-κB target genes, such as COX-2, TNFα, ICAM-1, and several interleukins. In contrast, hepatocytes derived from the PXR null mice showed elevated NF-κB target gene expressions compared to cells from the wild-type animals, suggesting that PXR plays a role in suppressing the NF-κB-regulated gene expression. Moreover, the PXR null mice exhibited signs of heightened inflammation in their small bowels (Zhou et al., 2006Zhou C. Tabb M.M. Nelson E.L. Grun F. Verma S. Sadatrafiei A. Lin M. Mallick S. Forman B.M. Thummel K.E. Blumberg B. J. Clin. Invest. 2006; 116: 2280-2289Crossref PubMed Scopus (299) Google Scholar). NF-κB belongs to a family of evolutionarily conserved eukaryotic transcription factors that are pivotal in regulating innate and adaptive immune responses (Ghosh et al., 1998Ghosh S. May M.J. Kopp E.B. Annu. Rev. Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4450) Google Scholar). In mammals, there are five known NF-κB proteins, all sharing a common 300 amino acid Rel homology domain. These include NF-κB1 (p50 and its precursor p105), NF-κB2 (p52 and its precursor p100), c-Rel, RelA (p65), and RelB. A typical NF-κB activation involves the heterodimerization of p65 and p50 and subsequent binding of p65/p50 heterodimers to NF-κB sites found in the target gene promoters. NF-κB proteins are normally sequestered in the cytoplasm by inhibitor of NF-κB (IκB). The NF-κB activation involves phosphorylation, ubiquitination and proteosome-dependent degradation of IκB and subsequent release of NF-κB for its nuclear translocation and transcriptional activity. NF-κB proteins are well known for their swift activation in response to endotoxin or proinflammatory cytokines. Activation of NF-κB, however, is not without a cost; the collateral damages include excessive inflammatory reactions that may be involved in septic shock, acute respiratory distress syndrome, unwanted antiapoptotic activity that may allow neoplasm to slip through, and decreases in xenobiotic/drug metabolism (Aitken et al., 2006Aitken A.E. Richardson T.A. Morgan E.T. Annu. Rev. Pharmacol. Toxicol. 2006; 46: 123-149Crossref PubMed Scopus (330) Google Scholar, Karin, 2006Karin M. Nature. 2006; 441: 431-436Crossref PubMed Scopus (2804) Google Scholar). Indeed, in this work, Zhou et al., 2006Zhou C. Tabb M.M. Nelson E.L. Grun F. Verma S. Sadatrafiei A. Lin M. Mallick S. Forman B.M. Thummel K.E. Blumberg B. J. Clin. Invest. 2006; 116: 2280-2289Crossref PubMed Scopus (299) Google Scholar showed that NF-κB activation inhibited PXR/SXR and its primary target gene CYP3A, whereas inhibition of NF-κB enhanced PXR/SXR-mediated activation of drug metabolizing enzymes. Interestingly, Zhou et al. reported that the increased inflammation in the PXR null mice appeared to be specific for the small bowel (Zhou et al., 2006Zhou C. Tabb M.M. Nelson E.L. Grun F. Verma S. Sadatrafiei A. Lin M. Mallick S. Forman B.M. Thummel K.E. Blumberg B. J. Clin. Invest. 2006; 116: 2280-2289Crossref PubMed Scopus (299) Google Scholar). The reason for this tissue specificity could be due to the loss of negative regulation of PXR on NF-κB, as suggested by these investigators. However, it is also possible that the inflammatory lesions were caused by inadequate metabolism and clearance of toxic xeno- and endobiotic substances from this tissue (Langmann et al., 2004Langmann T. Moehle C. Mauerer R. Scharl M. Liebisch G. Zahn A. Stremmel W. Schmitz G. Gastroenterology. 2004; 127: 26-40Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar). Intriguingly, a recent report suggests that reduced expression and/or functional polymorphisms of PXR/SXR are associated with inflammatory bowel diseases (IBD) (Dring et al., 2006Dring M.M. Goulding C.A. Trimble V.I. Keegan D. Ryan A.W. Brophy K.M. Smyth C.M. Keeling P.W. O'Donoghue D. O'Sullivan M. et al.Gastroenterology. 2006; 130: 341-348Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). This evidence collectively suggests that dysregulation of PXR/SXR expression or activity may predispose the GI track to inflammatory injuries. Although the mutual suppression between PXR/SXR and NF-κB was convincingly demonstrated by Zhou et al., 2006Zhou C. Tabb M.M. Nelson E.L. Grun F. Verma S. Sadatrafiei A. Lin M. Mallick S. Forman B.M. Thummel K.E. Blumberg B. J. Clin. Invest. 2006; 116: 2280-2289Crossref PubMed Scopus (299) Google Scholar, this study falls short in pinpointing the molecular linchpin that connects PXR/SXR and NF-κB signaling pathways. This deficiency, however, has been complemented by several studies published recently by other groups. In an effort to understand the suppression of CYP3A4 by proinflammatory agents, Gu and colleagues showed that NF-κB activation disrupted the binding of PXR/RXR heterodimers to a PXR response element (PXRE) found in the CYP3A4 gene promoter, providing a plausible molecular mechanism for the suppression of drug metabolism by proinflammatory signals (Gu et al., 2006Gu X. Ke S. Liu D. Sheng T. Thomas P.E. Rabson A.B. Gallo M.A. Xie W. Tian Y. J. Biol. Chem. 2006; 281: 17882-17889Crossref PubMed Scopus (238) Google Scholar). In the same study, NF-κB RelA/p65 was shown to interact with the highly conserved RXR DNA binding domain. This mode of suppression may have broad implications, as RXR is the obligate partner for xenobiotic receptors PXR and CAR as well as nonxenobiotic receptors, such as vitamin D receptor, which have also been implicated in xenobiotic metabolism. As an example of nuclear receptor-mediated suppression of NF-κB, recent work by Pascual et al. showed that ligand-dependent and residue-specific SUMOylation of PPARγ targeted this receptor to the promoter of iNOS, a NF-κB target gene. This PPARγ targeting prevented the removal of corepressor complex from the iNOS promoter, thus suppressing its positive regulation by NF-κB (Pascual et al., 2005Pascual G. Fong A.L. Ogawa S. Gamliel A. Li A.C. Perissi V. Rose D.W. Willson T.M. Rosenfeld M.G. Glass C.K. Nature. 2005; 437: 759-763Crossref PubMed Scopus (961) Google Scholar). It remains to be seen whether a similar mechanism is applicable in the suppression of NF-κB by PXR/SXR. Regardless of the molecular details of the interaction, the mutual repression between PXR/SXR and NF-κB manifests nature's "checks and balances" between two pathways that are at the heart of xenobiotic homeostasis and biodefense of an organism (Figure 1). Since PXR can also sense numerous endobiotics, it is interesting to know whether or not there is interplay between the endobiotic homeostasis and inflammatory responses. Whether the xenobiotic receptor-NF-κB cross-talk is conserved for CAR or other xenobiotic metabolism-implicating nuclear receptors is unknown. If the human relevance of the findings in Zhou et al., 2006Zhou C. Tabb M.M. Nelson E.L. Grun F. Verma S. Sadatrafiei A. Lin M. Mallick S. Forman B.M. Thummel K.E. Blumberg B. J. Clin. Invest. 2006; 116: 2280-2289Crossref PubMed Scopus (299) Google Scholar can be substantiated, one can envision that certain PXR ligands may be used to limit the intensity and duration of NF-κB activation in a tissue-specific manner, thus exerting anti-inflammatory action. Reciprocally, the suppression of the xenobiotic detoxification by inflammation in IBD can be reversed through inhibition of NF-κB activity, allowing PXR to retain its transcriptional activity.