Topical Rosiglitazone Treatment Improves Ulcerative Colitis by Restoring Peroxisome Proliferator-Activated Receptor-γ Activity

OBJECTIVES: Impaired epithelial expression of peroxisome proliferator-activated receptor-gamma (PPAR gamma) has been described in animal colitis models and briefly in patients with ulcerative colitis, but the functional significance in humans is not well defined. We examined PPAR gamma expression and functional activity in human colonic epithelium and explored the potential of topical treatment with rosiglitazone (a PPAR gamma ligand) in patients with ulcerative colitis. METHODS: Spontaneous and rosiglitazone-mediated PPAR gamma and adipophillin expression (a gene transcriptionally activated by PPAR gamma) were measured by reverse transcriptase PCR in colonic biopsies and isolated epithelial cells from patients with ulcerative colitis and controls. Fourteen patients with active distal ulcerative colitis were randomized to either rosiglitazone (4 mg) or mesalazine (1 g) enema treatment once daily for 14 days. RESULTS: PPAR gamma expression was fourfold reduced in epithelial cells from inflamed compared with uninflamed mucosa and controls. Adipophillin levels were decreased in parallel. Rosiglitazone induced a concentration-dependent increase in adipophillin levels and restored PPAR gamma activity in epithelial cells from inflamed mucosa in vitro. Rosiglitazone enema treatment was well tolerated and reduced the Mayo ulcerative colitis score from 8.9 to 4.3 (P < 0.01), similar to the effect of mesalazine. Rosiglitazone increased adipophillin levels in the epithelial cells of the patients, indicating PPAR gamma activation in vivo. CONCLUSIONS: Roziglitasone enemas improve impaired PPAR gamma activity in inflamed colonic epithelium and have beneficial clinical effect in patients with active distal ulcerative colitis. These findings raise interest in further studies of PPAR gamma ligands that exhibit their anti-inflammatory effect locally in the gut to avoid possible systemic side effects.