Local level of TGF-1 determines the effectiveness of dexamethasone through regulating the balance of Treg/Th17 cells in TNBS-induced mouse colitis

Transforming growth factor 1 (TGF-1) has a crucial role in regulating the balance of type 17 T-helper cells (Th17) and T regulatory cells (Tregs) that are involved in the pathogenesis of inflammatory bowel disease, while the function of local TGF-1 in this process has remained to be fully elucidated. The present study investigated the effects of different local TGF-1 levels on the Treg/Th17 balance and on the dexamethasone efficacy in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. Various TGF-1 levels in colon tissue were achieved by enema delivery of a high, medium or low amount of adenovirus expressing TGF-1 (10(7), 10(8) or 10(9) pfu, denoted as AdTGF-1, AdTGF-2 and AdTGF-3, respectively). Dexamethasone further decreased colon damage and myeloperoxidase activity in TNBS mice receiving AdTGF-1 and AdTGF-2. When AdTGF-1 was administered, dexamethasone enhanced its effect by reducing interferon (IFN)- and increasing interleukin (IL)-10 production. In TNBS mice receiving AdTGF-2, the increase in IFN-, tumor necrosis factor-, IL-6, IL-17 and IL-23 was significantly prevented by dexamethasone treatment. In comparison with the lower doses, AdTGF-3 exerted the opposite effect on regulating the cytokine production in TNBS mice, which was not affected by dexamethasone treatment. In mesenteric lymph nodes, AdTGF-1 prevented the TNBS-induced reduction of Tregs and IL-10, and potentially increased the efficacy of dexamethasone. In addition, dexamethasone further decreased the levels of activated caspase3 in TNBS mice receiving adenoviral TGF-1, particularly in the AdTGF-1 group. The activation of the p38 mitogen-activated protein kinase/c-Jun N-terminal kinase/c-Jun pathway was significantly inhibited by a low amount of TGF-1 administered to TNBS-treated mice, which was further decreased by dexamethasone. The present study provided evidence that the therapeutic effect of dexamethasone may depend on the local levels of TGF-1 in TNBS-induced colitis and may be mediated, at least partially, through promoting the differentiation of Tregs and thus altering the balance of pro- and anti-inflammatory cytokines.