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Xenobiotic Receptor Meets NF-Kb, a Collision in the Small Bowel

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Xenobiotic Receptor Meets NF-Kb, a Collision in the Small Bowel View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector PREVIEWS Xenobiotic receptor meets NF-kB, a collision in the small bowel It has long been appreciated that inflammation and infection reduce drug metabolism and that exposure to drug metabo- lism-inducing xenobiotics can impair immune function. A new study reveals the mutual repression between the xenobiotic nuclear receptor PXR/SXR and NF-kB signaling pathways, providing a molecular mechanism linking xenobiotic metabolism and inflammation (Zhou et al., 2006). Gene and environment interactions are a Xeno- and endobiotics that activate totic activity that may allow neoplasm vital force that constantly shape living PXR/SXR include various prescription to slip through, and decreases in xenobi- organisms. In dealing with xenobiotics, drugs, herbal medicines, environmental otic/drug metabolism (Aitken et al., 2006; mammals have evolved a defensive net- toxicants, and bile acids. Zhou and col- Karin, 2006). Indeed, in this work, Zhou work governed by the so-called xenobi- leagues demonstrated that drugs that et al. (2006) showed that NF-kB activa- otic receptors/xeno-senors, such as typically activate human PXR/SXR, such tion inhibited PXR/SXR and its primary pregnane X receptor (PXR, also known as rifampicin, suppressed the expression target gene CYP3A, whereas inhibition as steroid and xenobiotic receptor or of typical NF-kB target genes, such as of NF-kB enhanced PXR/SXR-mediated SXR) and constitutive androstane recep- COX-2, TNFa, ICAM-1, and several inter- activation of drug metabolizing enzymes. tor (CAR). When encountering infectious leukins. In contrast, hepatocytes derived Interestingly, Zhou et al. reported that agents, organisms have enlisted the in- from the PXR null mice showed elevated the increased inflammation in the PXR nate and adaptive immune defensive NF-kB target gene expressions com- null mice appeared to be specific for the systems, in which the nuclear factor pared to cells from the wild-type animals, small bowel (Zhou et al., 2006). The rea- kappa B (NF-kB) plays an essential regu- suggesting that PXR plays a role in sup- son for this tissue specificity could be latory role. Armed with the chemical and pressing the NF-kB-regulated gene ex- due to the loss of negative regulation of immunological defensive systems, mam- pression. Moreover, the PXR null mice PXR on NF-kB, as suggested by these mals by and large cope well with the exhibited signs of heightened inflam- investigators. However, it is also possi- challenge of noxious substances or in- mation in their small bowels (Zhou et al., ble that the inflammatory lesions were fectious agents that have been part of 2006). caused by inadequate metabolism and their life. However, these two defensive NF-kB belongs to a family of evolution- clearance of toxic xeno- and endobiotic systems do not always run in sync; in arily conserved eukaryotic transcription substances from this tissue (Langmann some cases one prevails at the cost of factors that are pivotal in regulating in- et al., 2004). Intriguingly, a recent report the other. It has been known in the clinic nate and adaptive immune responses suggests that reduced expression and/ that inflammation and infection reduce (Ghosh et al., 1998). In mammals, there or functional polymorphisms of PXR/SXR hepatointestinal drug metabolism ca- are five known NF-kB proteins, all shar- are associated with inflammatory bowel pacity (Aitken et al., 2006). Meanwhile, ing a common 300 amino acid Rel diseases (IBD) (Dring et al., 2006). This drug metabolism-inducing xenobiotics/ homology domain. These include NF-kB1 evidence collectively suggests that dys- drugs, such as the antibiotic rifampicin, (p50 and its precursor p105), NF-kB2 (p52 regulation of PXR/SXR expression or are known to repress the immune system and its precursor p100), c-Rel, RelA (p65), activity may predispose the GI track to (Paunescu, 1970). In the July issue of the and RelB. A typical NF-kB activation inflammatory injuries. Journal of Clinical Investigation, Zhou involves the heterodimerization of p65 Although the mutual suppression be- et al. demonstrated mutual suppression and p50 and subsequent binding of p65/ tween PXR/SXR and NF-kB was convinc- between PXR/SXR and NF-kB, providing p50 heterodimers to NF-kB sites found ingly demonstrated by Zhou et al. (2006), a potential molecular mechanism that in the target gene promoters. NF-kB this study falls short in pinpointing the links xenobiotic metabolism and inflam- proteins are normally sequestered in the molecular linchpin that connects PXR/ mation (Zhou et al., 2006). cytoplasm by inhibitor of NF-kB(IkB). The SXR and NF-kB signaling pathways. PXR/SXR was isolated as an orphan NF-kB activation involves phosphoryla- This deficiency, however, has been com- nuclear receptor that regulates the me- tion, ubiquitination and proteosome- plemented by several studies published tabolism and disposition of various xeno- dependent degradation of IkB and sub- recently by other groups. In an effort to biotics and endobiotics. The xeno-sen- sequent release of NF-kB for its nuclear understand the suppression of CYP3A4 sor function of PXR is achieved through translocation and transcriptional activity. by proinflammatory agents, Gu and col- its coordinated transcriptional regulation NF-kB proteins are well known for their leagues showed that NF-kB activation of Phase I and Phase II drug metabolizing swift activation in response to endotoxin disrupted the binding of PXR/RXR heter- enzymes as well as the ‘‘Phase III’’ drug or proinflammatory cytokines. Activation odimers to a PXR response element transporters (Xie et al., 2004). The flexibil- of NF-kB, however, is not without a cost; (PXRE) found in the CYP3A4 gene pro- ity in its ligand binding pocket enables the collateral damages include excessive moter, providing a plausible molecular PXR/SXR to function as a xenobiotic re- inflammatory reactions that may be in- mechanism for the suppression of drug ceptor through interacting with a wide volved in septic shock, acute respiratory metabolism by proinflammatory signals range of structurally diverse compounds. distress syndrome, unwanted antiapop- (Gu et al., 2006). In the same study, CELL METABOLISM : SEPTEMBER 2006 177 PREVIEWS be used to limit the intensity and duration of NF-kB activation in a tissue-specific manner, thus exerting anti-inflammatory action. Reciprocally, the suppression of the xenobiotic detoxification by inflam- mation in IBD can be reversed through inhibition of NF-kB activity, allowing PXR to retain its transcriptional activity. Wen Xie1 and Yanan Tian2 1 Center for Pharmacogenetics University of Pittsburgh Pittsburgh, Pennsylvania 15261 2 Department of Veterinary Physiology and Pharmacology Texas A&M University College Station, Texas 77843 Selected reading Aitken, A.E., Richardson, T.A., and Morgan, E.T. (2006). Annu. Rev. Pharmacol. Toxicol. 46,123– 149. Dring, M.M., Goulding, C.A., Trimble, V.I., Kee- Figure 1. Mutual repression between PXR/SXR and NF-kB signaling pathways gan, D., Ryan, A.W., Brophy, K.M., Smyth, C.M., The PXR/SXR and NF-kB mutual suppression may link xenobiotic metabolism and inflammation in the hepa- Keeling, P.W., O’Donoghue, D., O’Sullivan, M., tointestinal axis. IBD, inflammatory bowel disease; ICAM, intercellular adhesion molecule; LPS, lipopolysac- et al. (2006). Gastroenterology 130, 341–348. charide; NF-kB, nuclear factor kappa B; PXR, pregnane X receptor; PXRE, PXR response element; SXR, steroid and xenobiotic receptor; TNF, tumor necrosis factor. Ghosh, S., May, M.J., and Kopp, E.B. (1998). Annu. Rev. Immunol. 16, 225–260. Gu, X., Ke, S., Liu, D., Sheng, T., Thomas, P.E., NF-kB RelA/p65 was shown to interact mechanism is applicable in the suppres- Rabson, A.B., Gallo, M.A., Xie, W., and Tian, Y. with the highly conserved RXR DNA bind- sion of NF-kB by PXR/SXR. (2006). J. Biol. Chem. 281, 17882–17889. ing domain. This mode of suppression Regardless of the molecular details of Karin, M. (2006). Nature 441, 431–436. may have broad implications, as RXR is the interaction, the mutual repression be- Langmann, T., Moehle, C., Mauerer, R., Scharl, the obligate partner for xenobiotic recep- tween PXR/SXR and NF-kB manifests M., Liebisch, G., Zahn, A., Stremmel, W., and tors PXR and CAR as well as nonxenobi- nature’s ‘‘checks and balances’’ between Schmitz, G. (2004). Gastroenterology 127, 26–40. otic receptors, such as vitamin D recep- two pathways that are at the heart of Pascual, G., Fong, A.L., Ogawa, S., Gamliel, A., tor, which have also been implicated in xenobiotic homeostasis and biodefense Li, A.C., Perissi, V., Rose, D.W., Willson, T.M., xenobiotic metabolism. As an example of an organism (Figure 1). Since PXR can Rosenfeld, M.G., and Glass, C.K. (2005). Nature of nuclear receptor-mediated suppres- also sense numerous endobiotics, it is 437, 759–763. sion of NF-kB, recent work by Pascual interesting to know whether or not there Paunescu, E. (1970). Nature 228, 1188–1190. et al. showed that ligand-dependent and is interplay between the endobiotic ho- residue-specific SUMOylation of PPARg meostasis and inflammatory responses. Xie, W., Uppal, H., Saini, S.P., Mu, Y., Little, J.M., Radominska-Pandya, A., and Zemaitis, M.A. targeted this receptor to the promoter of Whether the xenobiotic receptor-NF-kB (2004). Drug Discov. Today 9, 442–449. iNOS, a NF-kB target gene. This PPARg cross-talk is conserved for CAR or other targeting prevented the removal of core- xenobiotic metabolism-implicating nu- Zhou, C., Tabb, M.M., Nelson, E.L., Grun, F., Verma, S., Sadatrafiei, A., Lin, M., Mallick, S., pressor complex from the iNOS pro- clear receptors is unknown. If the human Forman, B.M., Thummel, K.E., and Blumberg, moter, thus suppressing its positive regu- relevance of the findings in Zhou et al.
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