Impaired expression of peroxisome proliferator-activated receptor γ in ulcerative colitis

doi:10.1016/S0016-5085(03)00271-3

Gastroenterology

Volume 124, Issue 5, May 2003, Pages 1265-1276

https://doi.org/10.1016/S0016-5085(03)00271-3 Get rights and content

Abstract

Background & Aims:

The peroxisome proliferator-activated receptor γ (PPARγ) has been proposed as a key inhibitor of colitis through attenuation of nuclear factor κB (NF-κB) activity. In inflammatory bowel disease, activators of NF-κB, including the bacterial receptor toll-like receptor (TLR)4, are elevated. We aimed to determine the role of bacteria and their signaling effects on PPARγ regulation during inflammatory bowel disease (IBD).

Methods:

TLR4-transfected Caco-2 cells, germ-free mice, and mice devoid of functional TLR4 (Lps^d/Lps^d mice) were assessed for their expression of PPARγ in colonic tissues in the presence or absence of bacteria. This nuclear receptor expression and the polymorphisms of gene also were assessed in patients with Crohn’s disease (CD) and ulcerative colitis (UC), 2 inflammatory bowel diseases resulting from an abnormal immune response to bacterial antigens.

Results:

TLR4-transfected Caco-2 cells showed that the TLR4 signaling pathway elevated PPARγ expression and a PPARγ-dependent reporter in an Iκκβ dependent fashion. Murine and human intestinal flora induced PPARγ expression in colonic epithelial cells of control mice. PPARγ expression was significantly higher in the colon of control compared with Lps^d/Lps^d mice. Although PPARγ levels appeared normal in patients with CD and controls, UC patients displayed a reduced expression of PPARγ confined to colonic epithelial cells, without any mutation in the PPARγ gene.

Conclusions:

These data showed that the commensal intestinal flora affects the expression of PPARγ and that PPARγ expression is considerably impaired in patients with UC.

Section snippets

Transient transfections in cell lines

The colon carcinoma cell line Caco-2 (ATCC HTB-37) was used for all transient transfections and RNA expression analysis. Caco-2 cells were transfected using the FuGENE transfection reagent according to the manufacturer (Roche Diagnostics Corporation, Indianapolis, IN) and RNA was prepared after 48 hours. The luciferase assay (SDS/Promega, Madison, WI) was used according to instructions from the manufacturer. SDS/Promega describes all reporter gene constructs, the Tk-promoter-luciferase from

TLR4 can regulate peroxisome proliferator-activated receptor γ expression in colonic epithelial cells

To assess whether a TLR4-mediated signal could affect PPARγ expression, Caco-2 cells were used because this particular cell line has low baseline levels of TLR4 expression.26 The cells were stimulated with LPS for 24 hours and PPARγ expression was monitored by an RPA. As shown in Figure 1A , LPS significantly up-regulated the expression of PPARγ by approximately 3-fold compared with cells transfected with an empty vector. The up-regulation of PPARγ was observed after 24 hours and it is

Discussion

Intestinal colonic epithelial cells are an important barrier between luminal bacteria and the adaptive immune cells of the lamina propria. The epithelial lining represents a well-documented player in mucosal homeostasis. These cells secrete many mediators such as cytokines or chemokines in response to bacterial triggering, in part via the TLR4 receptor.33 As much as these cells secrete all the mediators—to promote inflammation—they may do so in their sole purpose to ensure induction of repair

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^☆: Supported by grants from IRMAD, the association F. Aupetit, syndifrais, the Centre Hospitalier et Universitaire de Lille (EA2687, CA14555, and PHRC1926), the Fondation pour la Recherche Médicale (to L. D. and P. D.); Foundation for Knowledge and Competence Development, Swedish Strategic Foundation and Cancerfonden Sweden (to E. Å. J.); the National Institutes of Health grant number HL-64322 (to S. P. and S. S. D.); INSERM, CNRS, Hôpitaux Universitaires de Strasbourg, and the European Union (GLRT-1999-00679 and GLRT-2001-00930) (to J. A.).

¹: The authors thank C. Bisiaux for her valuable technical assistance and Marie-Christiane Moreau and Philippe Podevin who provided mice with different flora, and C3H/HeJ (Lps^d/Lps^d) and C3H/HeouJ (Lpsⁿ/Lpsⁿ) mice, respectively. The authors also thank Drs. Cyrus Tamboli and William J. Sandborn for critical reading of the manuscript.

²: L. D. and E. Å. J. contributed equally to this work.

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Clinical-alimentary tractImpaired expression of peroxisome proliferator-activated receptor γ in ulcerative colitis☆

Abstract

Background & Aims:

Methods:

Results:

Conclusions:

Section snippets

Transient transfections in cell lines

TLR4 can regulate peroxisome proliferator-activated receptor γ expression in colonic epithelial cells

Discussion

Eur J Radiol

Lancet

J Nutr

J Immunol Methods

Gastroenterology

Gastroenterology

J Biol Chem

Mol Cell

Biochem Biophys Res Commun

J Biol Chem

J Autoimmun

Gastroenterology

Am J Pathol

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Am J Gastroenterol

Peroxisome proliferator-activated receptors, orphans with ligands and functions

Curr Opin Lipidol

The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation

Nature

PPARγ agonists inhibit production of monocyte inflammatory cytokines

Nature

Peroxisome proliferator-activated receptor gamma is induced during differentiation of colon epithelium cells

J Endocrinol

A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response

J Clin Invest

Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies

J Exp Med

Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing toll-like receptors

J Immunol

Clinical-alimentary tract
Impaired expression of peroxisome proliferator-activated receptor γ in ulcerative colitis☆