Background: Intestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohnâ��s\ndisease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated\nthat peroxisome proliferator-activated receptor- �³ (PPAR-�³) agonists have anti-fibrogenic properties in\norgans besides the gut; however, their effects on human intestinal fibrosis are poorly understood.\nThis study investigated the anti-fibrogenic properties and mechanisms of PPAR-�³ agonists on human\nprimary intestinal myofibroblasts (HIFs).\nMethods: HIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer.\nHIFs were treated with TGF-�²1 and co-incubated with or without one of two synthetic PPAR-�³ agonists, troglitazone\nor rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and �±-smooth muscle actin were\ndetermined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt\ninhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-�²1 induced\nexpression of procollagen1A1, fibronectin, and �±-smooth muscle actin in HIFs. The irreversible PPAR-�³ antagonist\nGW9662 was used to investigate whether the effect of PPAR-�³ agonists was PPAR-�³ dependent.\nResults: Both PPAR-�³ agonists reduced the TGF-�²1-induced expression of �±-smooth muscle actin which was\nintegrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and �±-smooth muscle\nactin-specific immunocytochemistry. PPAR-�³ agonists also inhibited TGF-�²1-induced mRNA and protein expressions of\nprocollagen1A1, fibronectin, and �±-smooth muscle actin. TGF-�²1 stimulation increased phosphorylation of downstream\nsignaling molecules Smad2, Akt, and ERK. TGF-�²1 induced synthesis of procollagen1A1, fibronectin, and �±-smooth\nmuscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-�³ agonists down regulated\nfibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-�³\nindependent.\nConclusions: Troglitazone and rosiglitazone suppress TGF-�²1-induced synthesis of procollagen1A1, fibronectin, and\n�±-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis.
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