Pioglitazone, a PPAR-gamma ligand, provides protection from dextran sulfate sodium-induced colitis in mice in association with inhibition of the NF-kappaB-cytokine cascade.
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.
Takagi
Tomohisa
T
First Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Naito
Yuji
Y
Tomatsuri
Naoya
N
Handa
Osamu
O
Ichikawa
Hiroshi
H
Yoshida
Norimasa
N
Yoshikawa
Toshikazu
T
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001835:Body Weight; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy; D003106:Colon / Q000473:pathology; D004247:DNA / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology*; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D000077205:Pioglitazone; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
D000925:Anticoagulants; D007004:Hypoglycemic Agents; D008024:Ligands; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D017392:Thiobarbituric Acid Reactive Substances; D014157:Transcription Factors; D004247:DNA; D016264:Dextran Sulfate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000077205:Pioglitazone