Local level of TGF-β1 determines the effectiveness of dexamethasone through regulating the balance of Treg/Th17 cells in TNBS-induced mouse colitis

You,Peng; Chen,Ning; Su,Lin; Peng,Tao; Chen,Guodong; Liu,Yulan

doi:10.3892/etm.2018.5852

Local level of TGF-β1 determines the effectiveness of dexamethasone through regulating the balance of Treg/Th17 cells in TNBS-induced mouse colitis

Authors:
- Peng You
- Ning Chen
- Lin Su
- Tao Peng
- Guodong Chen
- Yulan Liu
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Affiliations: Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, P.R. China
Published online on: February 8, 2018 https://doi.org/10.3892/etm.2018.5852
Pages: 3639-3649

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Abstract

Transforming growth factor β1 (TGF-β1) 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‑β1 in this process has remained to be fully elucidated. The present study investigated the effects of different local TGF‑β1 levels on the Treg/Th17 balance and on the dexamethasone efficacy in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)‑induced colitis. Various TGF‑β1 levels in colon tissue were achieved by enema delivery of a high, medium or low amount of adenovirus expressing TGF‑β1 (107, 108 or 109 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)‑γ and increasing interleukin (IL)‑10 production. In TNBS mice receiving AdTGF‑2, the increase in IFN‑γ, tumor necrosis factor‑α, 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‑β1, 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‑β1 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‑β1 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.

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