Pregnane X receptor as a target for treatment of inflammatory bowel disorders

Abstract

Pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, has a major role in the induction of genes involved in drug transport and metabolism. Recent studies in mice have provided insight into a novel function for PXR in inflammatory bowel disease (IBD). The mechanism of the protective effect of PXR activation on IBD is not fully established, but is due in part to the attenuation of nuclear factor (NF)-κB signaling that results in lower expression of proinflammatory cytokines. Recent clinical trials with the antibiotic rifaximin, a PXR agonist in the gastrointestinal system, have revealed its potential therapeutic value in the treatment of intestinal inflammation in humans. Thus, PXR may be a novel target for IBD therapy.

Fig 1. Rifaximin repression of IBD via human PXR regulation

Chemically-induced IBD destroys the structure and function of normal epithelial cells and expression of DMEs (A), due in part to activation of NF-κB and increased proinflammatory cytokines. (B) following an imbalance of the epithelial barrier and mucosal immune system and increase of intestinal permeability. However, upon rifaximin-induced PXR activation in epithelial cells, the NF-κB signaling cascade is repressed and cytokine production is inhibited, associated with suppression of intestinal permeability through PXR activation. This restores the balance between the epithelial barrier and mucosal immune system, resulting in the reconstruction of cell structure and function (C). DMEs: drug metabolism enzymes.

Fig 2. The cross-inhibition between PXR and NF-κB

NF-κB contains two major components, p65 and p50. PXR/RXR heterodimer auto-bind with CBP, PCAF and HAT initially to regulate transcription. NF-κB can directly interact with the RXR. Thus, one possibility to explain the link between NF-κB and PXR is through the binding of p65 and RXR. This binding is triggered upon ligand binding of PXR response element. The binding between p65 and RXR may also interfere with the formation of the p65-p50 complex and subsequent DNA binding. CBP: CREB-binding protein, PCAF: P300/CBP-associated factor, HAT: histone acetyltransferase, H3/H4: histones. Cytokines are IL-8: interleukin 8, IκBα: IκBα-NFκB complex, IFNβ: interferon-beta, MCP-1: monocyte chemotactic protein-1, TNFα: tumor necrosis factors alpha.

Fig 3. Multiple signaling cascades to repress IBD via PXR modulation

Crosstalk between PXR and NF-κB, through direct action of PXR by ubiquitylation, phosphorylation, SUMOylation, and acetylation could impact inflammation (I), as well as germline-encoded pattern recognition receptors (PRR, including TLR/NOD2) activation of JNK or IKK by LPS resulting in the modification of RXRα, leading to suppression of PXR/RXRα-dependent hepatic genes (DMEs, drug metabolism enzymes) (II). In addition, PXR inhibits T lymphocyte proliferation by decreasing expression of cytokines of CD25 and IFNγ and decreasing phosphorylation of NF-κB in mouse and human T lymphocytes (III). JNK: c-Jun NH(2)-terminal kinase, IKK: IκB kinase, CD25:alpha chain of the IL-2 receptor, IFNγ: Interferon-gamma.