Rifaximin Protection of DSS‐Induced Inflammatory Bowel Disease by Inhibition of Nuclear Factor Kappa B through Activation of Human Pregnane X Receptor

Background: Inflammatory bowel disease (IBD) is a multifactorial condition influenced by the immune system, the intestinal microbiota, environmental factors, genetic and epigenetic factors. Genetic- and environment-induced dysregulation of the Nuclear Factor-kappa B (NF-κB) transcription factor pathway has been linked to IBD pathogenesis. Objective: To assess the current evidence in relation to the contribution of the classical and alternative NF-κB pathways in IBD and to discuss the epigenetic mechanisms that impact on NF-κB function. Methods: A Medline search for ‘NF-kappaB/NF-κB’, in combination with terms including ‘inflammatory bowel disease/IBD’, 'intestinal inflammation', ‘Crohn's disease’, ‘ulcerative colitis’, 'colitis'; ‘epigenetics’, ‘DNA methylation’, ‘histones’, ‘microRNAs/miRNAs’ and ‘short non-coding/long non-coding RNAs’ was performed. Results: Both NF-κB pathways contribute to the chronic inflammation underlying IBD by regulating the inflammatory immune responses and homeostasis of the intestinal epithelium (classical pathway) or regulating bowel inflammation and epithelial microfold (M) cell function (alternative pathway). DNA methylation is a common epigenetic modification in intestinal inflammation, including NFKB1 and RELA loci. Conversely, little is understood regarding epigenetic effects on genes encoding other NF-κB subunits, particularly those of the alternative pathway, and in the context of IBD. However, NF-κB interaction with chromatin modifiers is also seen to be an essential mechanism of regulation of downstream target genes relevant to NF-κB-mediated inflammatory responses. Conclusion: Further research is clearly warranted in this area, as understanding the cell-specific regulation of the NF-κB pathways will bring researchers into a position to achieve more efficient stratification of IBD patients, and more targeted and effective choice of treatment.

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Activation of nuclear factor kappa B in inflammatory bowel disease

Gut ◽

10.1136/gut.42.4.477 ◽

1998 ◽

Vol 42 (4) ◽

pp. 477-484 ◽

Cited By ~ 489

Author(s):

S Schreiber ◽

S Nikolaus ◽

J Hampe

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Nuclear Factor Kappa B ◽

Nuclear Factor ◽

Nuclear Factor Kappa ◽

Inflammatory Bowel

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Liver X Receptor Exerts Anti-Inflammatory Effects in Colonic Epithelial Cells via ABCA1 and Its Expression Is Decreased in Human and Experimental Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab034 ◽

2021 ◽

Author(s):

José Miranda-Bautista ◽

Juan A Rodríguez-Feo ◽

Marta Puerto ◽

Beatriz López-Cauce ◽

José M Lara ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Epithelial Cells ◽

Bowel Disease ◽

Target Gene ◽

Nuclear Factor Kappa B ◽

Intestinal Epithelial Cells ◽

Nuclear Factor ◽

Intestinal Epithelial ◽

Inflammatory Bowel ◽

Anti Inflammatory

Abstract Background Liver X receptor (LXR) exerts anti-inflammatory effects in macrophages. The aim of this study was to explore the expression and function of LXR in the colonic epithelium under inflammatory conditions. Methods The expression of LXR was explored by Western blot and immunohistochemistry in colonic biopsies from patients diagnosed with inflammatory bowel disease (IBD) and control patients. In addition, LXR and its target gene expression were analyzed in the colon from interleukin (IL)-10-deficient (IL-10-/-) and wild-type mice. Caco-2 cells were pretreated with the synthetic LXR agonist GW3965 and further challenged with IL-1β, the expression of IL-8 and chemokine (C-C motif) ligand (CCL)-28 chemokines, the activation of mitogen-activated protein (MAP) kinases, and the nuclear translocation of the p65 subunit of nuclear factor kappa B was evaluated. Glibenclamide was used as an ABCA1 antagonist. Results We found that LXR expression was downregulated in colonic samples from patients with IBD and IL-10-/- mice. The nuclear positivity of LXR inversely correlated with ulcerative colitis histologic activity. Colonic IL-1β mRNA levels negatively correlated with both LXRα and LXRβ in the colon of IL-10-/- mice, where a decreased mRNA expression of the LXR target genes ABCA1 and FAS was shown. In addition, IL-1β decreased the expression of the LXR target gene ABCA1 in cultured intestinal epithelial cells. The synthetic LXR agonist GW3965 led to a decreased nuclear positivity of the p65 subunit of nuclear factor kappa B, a phosphorylation ratio of the p44-42 MAP kinase, and the expression of CCL-28 and IL-8 in IL-1β-stimulated Caco-2 cells. The pharmacological inhibition of ABCA1 increased the phosphorylation of p44-42 after GW3965 treatment and IL-1β stimulation. Conclusions The LXR-ABCA1 pathway exerts anti-inflammatory effects in intestinal epithelial cells and is impaired in the colonic mucosa of patients with IBD and IL-10-/- mice.

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Time-Resolved Effect of Interferon-Alpha 2a on Activities of Nuclear Factor Kappa B, Pregnane X Receptor and on Drug Disposition Genes

Pharmaceutics ◽

10.3390/pharmaceutics13060808 ◽

2021 ◽

Vol 13 (6) ◽

pp. 808

Author(s):

Dirk Theile ◽

Lelia Wagner ◽

Cindy Bay ◽

Walter Emil Haefeli ◽

Johanna Weiss

Keyword(s):

Mrna Expression ◽

Interferon Alpha ◽

Nuclear Factor Kappa B ◽

Drug Disposition ◽

Pregnane X Receptor ◽

Nuclear Factor ◽

Cyp3a4 Activity ◽

Time Resolved ◽

Nuclear Factor Kappa ◽

Disposition Genes

Interferon-alpha (IFN-α) is suggested to cause pharmacokinetic drug interactions by lowering expression of drug disposition genes through affecting the activities of nuclear factor kappa B (NF-ĸB) and pregnane X receptor (PXR). The time-resolved impact of IFN-α 2a (1000 U/mL; 5000 U/mL; 2 h to 30 h) on the activities of NF-ĸB and PXR and mRNA expression (5000 U/mL; 24 h, 48 h) of selected drug disposition genes and on cytochrome P450 (CYP3A4) activity in LS180 cells (5000 U/mL; 24 h, 48 h) was evaluated using luciferase-based reporter gene assays, reverse transcription polymerase chain reaction, and luminescence-based CYP3A4 activity assays. The cross-talk between NF-ĸB activation and PXR suppression was evaluated by NF-ĸB blockage (10 µM parthenolide). IFN-α 2a initially (2 h, 6 h) enhanced NF-ĸB activity 2-fold and suppressed PXR activity by 30%. mRNA of CYP3A4 was halved, whereas UGT1A1 was increased (1.35-fold) after 24 h. After 48 h, ABCB1 expression was increased (1.76-fold). CYP3A4 activity remained unchanged after 24 h, but was enhanced after 48 h (1.35-fold). IFN-α 2a demonstrated short-term suppressive effects on PXR activity and CYP3A4 mRNA expression, likely mediated by activated NF-ĸB. Longer exposure enhanced CYP3A4 activity. Clinical trials should evaluate the relevance by investigating the temporal effects of IFN-α on CYP3A4 using a sensitive marker substrate.

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