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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0803978v1 183/10/6251    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Vavassori, P. Articles by Fiorucci, S. PubMed PubMed Citation Articles by Vavassori, P. Articles by Fiorucci, S.

The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity¹

Piero Vavassori,^* Andrea Mencarelli,^* Barbara Renga,^* Eleonora Distrutti, and Stefano Fiorucci^2*

^*Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Perugia, Italy and Azienda Ospedaliera Santa Maria della Misericordia, Perugia, Italy

The farnesoid X receptor (FXR) is a bile acid-regulated nuclear receptor expressed in enterohepatic tissues. In this study we investigated whether FXR is expressed by cells of innate immunity and regulates inflammation in animal models of colitis. Acute (7 days) and chronic (8 wk) colitis were induced in wild-type and FXR^–/– mice by intrarectal administration of trinitrobenzensulfonic acid or by 7-day administration of 5% dextran sulfate in drinking water. The results of this experiment demonstrate that FXR is expressed by and exerts counterregulatory effects on cells of innate immunity. Exposure of LPS-activated macrophages to 6-ethyl chenodeoxycholic acid (6E-CDCA; INT-747) a synthetic FXR ligand, results in a reciprocal regulation of NF-B dependent-genes (TNF-, IL-1β, IL-6, COX-1, COX-2, and iNOS) and induction of SHP, a FXR-regulated gene. FXR activation stabilizes the nuclear corepressor NCoR on the NF-B responsive element on the IL-1β promoter. Colon inflammation in Crohn’s disease patients and in rodent models of colitis is associated with a reduced expression of FXR mRNA. Using two rodent models of colon inflammation, we show that progression of these immune-mediated disorders is exacerbated in FXR^–/– mice (p < 0.01). In vivo treatment with INT-747 attenuates organ injury and immune cell activation. FXR activation increased the colon expression of I-BABP, FXR, and SHP while reducing IL-1β, IL-2, IL-6, TNF-, and IFN- mRNA expression and attenuating disease severity. In aggregate, these findings provide evidence that FXR is an essential component of a network of nuclear receptors that regulate intestinal innate immunity and homeostasis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was partially supported by a grant from Intercept Pharmaceuticals Inc. to Stefano Fiorucci.

² Address correspondence and reprint requests to Dr. Stefano Fiorucci, Dipartimento di Medicina Clinica e Sperimentale, Via Enrico dal Pozzo, 06122 Perugia, Italy. E-mail address: fiorucci{at}unipg.it

³ Abbreviations used in this paper: NR, nuclear receptor; CDCA, chenodeoxycholic acid; ChIP, chromatin immunoprecipitation; COX, cyclooxygenase; DSS, dextran sulfate; FXR, farnesoid X receptor; I-BABP, intestinal bile acid-binding protein; iNOS, inducible NO synthase; LP, lamina propria; LBD, ligand binding domain; NcoR, nuclear compressor; PBDM, peripheral blood-derived macrophage; PPAR, peroxisome proliferator-activated receptor; qRT-PCR, quantitative RT-PCR; siRNA, small interfering RNA; SHP, Src homology region 2 domain-containing phosphatase; SUMO, small ubiquitin-like modifier; TNBS, trinitrobenzenesulfonic acid.

⁴ The online version of this article contains supplemental material.