Pioglitazone, a PPAR-γ ligand, provides protection from dextran sulfate sodium-induced colitis in mice in association with inhibition of the NF-κB-cytokine cascade

Abstract

Nuclear factor-kappaB-dependent up-regulation of inflammatory cytokines occurs in inflammatory bowel disease. We investigated the effect of pioglitazone, a peroxisome proliferator-activated receptor-gamma ligand, on dextran sulfate sodium-induced colonic mucosal injury and inflammation in mice. Acute colitis was induced in female mice receiving 0, 1, 3, and 10 mg/kg i.p. of pioglitazone daily. Colonic mucosal inflammation was evaluated chemically and histologically. Thiobarbituric acid-reactive substances and tissue-associated myeloperoxidase activity were measured in intestinal mucosa as indices of lipid peroxidation and neutrophil infiltration, respectively. Colonic mRNA expression of pro-inflammatory cytokines and inducible nitric oxide synthase was measured by reverse transcription-PCR and nuclear factor-kappaB activation was evaluated by electrophoretic mobility shift assay. Dextran sulfate sodium administration resulted in decreases in body weight and colon length and increases in lipid peroxide and neutrophil accumulation of the intestine. In contrast, co-administration with pioglitazone prevented these changes. Transcripts coding for pro-inflammatory cytokines and inducible nitric oxide were expressed in high levels after the development of colitis, and pioglitazone markedly reduced mRNA expression of these genes. DNA binding activity of nuclear factor-kappaB was markedly increased, whereas in pioglitazone co-treated intestines the effect was significantly reduced. These data suggest that peroxisome proliferator-activated receptor-gamma may be a novel therapeutic target for the therapy of inflammatory bowel disease.

Oxidized fat induces oxidative stress but has no effect on NF-κB-mediated proinflammatory gene transcription in porcine intestinal epithelial cells

“…NF-kB plays a key role in inflammatory diseases due to its ability to bind specifically to NF-kB-response elements in the promoters of key inflammatory genes (e. g. COX-2, iNOS, TNFa, and IL-6) and induce their gene transcription [12], which also explains why inhibition of NF-kB often ameliorates the pathology of these diseases [12,15,17,18]. Thus, the finding that DNA-binding activity of NF-kB as well as NF-kB target gene expression in intestinal epithelial cells were not altered by dietary oxidized fat probably indicates that the moderate PPARg activating effect of dietary oxidized fat has no implication for proinflammatory gene transcription in intestinal epithelial cells.…”

“…Modulation of inflammatory responses by PPARg is mediated by negatively interfering with a variety of signalling pathways such as nuclear factor-kappa B (NF-kB) [11], which leads to the repression of transcription of genes involved in inflammation [12]. This transrepression activity likely constitutes the mechanistic basis for the anti-inflammatory properties of PPARg and probably also explains why pharmacological PPARg-ligands markedly reduce inflammation in animal models of inflammatory colitis [13][14][15][16][17]. Conjugated linoleic acids, a group of naturally occurring polyunsaturated fatty acids, were also recently shown to ameliorate experimental colitis through a PPARg-dependent mechanism [18], indicating that dietary fatty acids are indeed capable of mediating PPARg-dependent effects in vivo.…”

β-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis in Mice through CB2 Receptor Activation and PPARγ Pathway

“…13,44 Indeed, PPAR␥ agonists ameliorate experimental colitis, [45][46][47] and PPAR␥ expression is reduced in patients with ulcerative colitis. 20 To verify whether PPAR␥ was also involved in colitis improvement after BCP treatment, the PPAR␥ antagonist GW9662 (1 mg/kg, i.p.)…”

Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF- B decoy oligonucleotides

“…These include agents derived from plants (catalposide, fucoidan, or curcumin) (47)(48)(49), low-molecular-weight molecules such as the MAPKs and RICK inhibitor (SB203580), the rho kinase inhibitor (Y27632), the PPARγ ligand (pioglitazone), and gliotoxin (50)(51)(52)(53). For the most part, these inhibitors have been tested in studies of either dextran sulphate sodium-induced colitis or hapten-induced colitis, in which their capacities to prevent mucosal inflammatory disease were assessed rather than their capacities to reverse established inflammatory disease, a more stringent test.…”