Attenuation of Colonic Inflammation by PPARγ in Intestinal Epithelial Cells: Effect on Toll-like Receptor Pathway

Abstract

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor highly expressed in the colon and playing an anti-inflammatory role through inhibition of the NF-kappaB pathway. Toll-like receptor 4 (TLR4) has been known to mediate LPS-induced cellular signaling through activation of NF-kappaB pathway in intestinal epithelial cells. The aims of this study were to evaluate attenuation of inflammation by PPARgamma in intestinal epithelial cells and to study the possible relation between PPARgamma and TLR4. HT-29 human epithelial cells were stimulated with LPS (20 microg/ml) and PPARgamma ligand, 15d-PGJ2 (10 microM), or with LPS (20 microg/ml) alone for 24 hr. COX-2, IL-8, TLR4, and PPARgamma mRNA expression was assessed by RT-PCR. IL-8 protein levels and TLR4 protein expression were analyzed by ELISA and Western blot, respectively. To evaluate the action mechanisms of PPARgamma ligand, Western blot analysis for IkappaBalpha degradation was performed. Costimulation with LPS and PPARgamma ligand in comparison to LPS stimulation alone (1) decreased COX-2, IL-8 mRNA expression and IL-8 protein secretion, (2) decreased TLR4 mRNA and protein expression, and (3) decreased PPARgamma mRNA expression. PPARgamma ligand delayed LPS-induced IkappaBalpha degradation. These findings suggest that PPAR-gamma ligands suppress inflammation in intestinal epithelial cells. PPARgamma and TLR, these two antagonistic signaling pathways in intestinal epithelial cells may be partially cross-linked.

Expression of PPARγ and PTEN in human colorectal cancer: An immunohistochemical study using tissue microarray methodology

“…Correlations between the expression of PPARγ or PTEN and the clinicopathological data in the CRC patients. difference was observed, consistent with the study by Eun et al (19). Therefore, in combination with the results of previous studies and our investigations, we propose that the colorectal basal cells decreased in fissionability and developed differentiated potential followed by the increased expression of PPARγ during the differentiation process.…”

“…Although it has been identified in other cancer cells, including prostate, gastric, pancreatic and lung cancer, but found to be absent from their corresponding benign tissues (13)(14)(15)(16), PPARγ was found to be expressed ubiquitously in colorectal epithelial cells and cancer cells by certain authors (17)(18)(19). The first problem to be addressed in the study is therefore the exact expression status of PPARγ in various colorectal specimens.…”

Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague–Dawley rats

“…LPS can increase PPAR-γ mRNA and treatment with a PPAR-γ agonist prevents this increase [14]. Therefore, a potential role for PPAR-γ mediated signaling may exist in our model.…”

“…PPAR-γ is found in the striatum [27] and its expression can be altered by LPS [12,14]. In addition, pioglitazone protects against LPS toxicity [22].…”

Cross-talk between nuclear receptors and nuclear factor κB

“…For instance, activation of PPARg in macrophages and foam cells inhibits the expression of activated pro-inflammatory NF-kB target genes such as inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP9) and scavenger receptor A. PPARg may also affect the recruitment of monocytes to atherosclerotic lesions (Neve et al, 2000) and can suppress inflammation in intestinal epithelial cells (Eun et al, 2006). A novel anti-inflammatory mechanism in the gut involves PPARg-dependent increased nuclear export of transcriptionally active NF-kB (Kelly et al, 2004).…”