Review
Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine

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Abstract

Hyperactivation of NF-κB is a key factor in the pathophysiology of inflammatory bowel disease (IBD). We previously showed that the bile salt nuclear Farnesoid X Receptor (FXR) counter-regulates intestinal inflammation, possibly via repression of NF-κB. Here, we examine whether mutual antagonism between NF-κB and FXR exists. FXR and its target genes IBABP and FGF15/19 expression were determined in HT29 colon carcinoma cells and ex vivo in intestinal specimens of wild type (WT) and Fxr-ko mice, treated with/without FXR ligands (GW4064/INT-747) and inflammatory stimuli (TNFα/IL-1β). In addition, FXR activation was studied in vivo in WT and Fxr-ko mice with DSS-colitis. The involvement of NF-κB in decreasing FXR activity was investigated by reporter assays and Glutathione S-transferase pulldown assays. FXR target gene expression was highly reduced by inflammatory stimuli in all model systems, while FXR mRNA expression was unaffected. In line with these results, reporter assays showed reduced FXR transcriptional activity upon TNFα/IL-1β stimulation. We show that this reduction in FXR activity is probably mediated by NF-κB, since overexpression of NF-κB subunits p50 and/or p65 also lead to inhibition of FXR activity. Finally, we report that p65 and p50 physically interact with FXR in vitro. Conclusions: Together, these results indicate that intestinal inflammation strongly reduces FXR activation, probably via NF-κB-dependent tethering of FXR. Therefore, FXR not only inhibits inflammation, but also is targeted by the inflammatory response itself. This could result in a vicious cycle where reduced FXR activity results in less repression of inflammation, contributing to development of chronic intestinal inflammation. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

Research highlights

► TNFα decreases FXR target gene expression in differentiated HT29 intestinal cells. ► TNFα and IL-1β decrease ileal FXR target gene expression ex vivo in WT mice. ► In the DSS model of murine colitis, FXR target gene expression is decreased. ► TNFα, IL-1β and overexpression of NF-κB subunits P50/P65 decrease FXR transcriptional activity. ► Intestinal inflammation inhibits FXR activation, probably via NF-κB-dependent tethering of FXR.

Abbreviations

BDL
bile duct ligation
CD
Crohn disease
DSS
dextran sodium sulfate
EV
empty vector
FGF
fibroblast growth factor
FXR
farnesoid X receptor
GAPDH
glyceraldehyde 3-phosphate dehydrogenase
GST
glutathione S-transferase
IBABP
intestinal bile acid binding protein
IBD
inflammatory bowel disease
IL
interleukin
KO
knock-out
NF-κB
nuclear factor κappa B
NR
nuclear receptor
RXR
retinoid X receptor
SHP
small heterodimer partner
TNBS
trinitrobenzene sulphonic acid
TNFα
tumor necrosis factor alpha
UC
ulcerative colitis
WT
wild type

Keywords

Inflammatory bowel disease
Nuclear factor κB
Farnesoid X Receptor
Mutual inhibition

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This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

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These authors share last authorship.