Topical Rosiglitazone Treatment Improves Ulcerative Colitis by Restoring Peroxisome Proliferator-Activated Receptor-γ Activity
OBJECTIVES:Impaired epithelial expression of peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ expression and functional activity in human colonic epithelium and explored the potential of topical treatment with rosiglitazone (a PPARγ ligand) in patients with ulcerative colitis.METHODS:Spontaneous and rosiglitazone-mediated PPARγ and adipophillin expression (a gene transcriptionally activated by PPARγ) 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:PPARγ 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 PPARγ 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 PPARγ activation in vivo.CONCLUSIONS:Roziglitasone enemas improve impaired PPARγ 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 PPARγ ligands that exhibit their anti-inflammatory effect locally in the gut to avoid possible systemic side effects.