You Peng, Chen Ning, Su Lin, Peng Tao, Chen Guodong, Liu Yulan
Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, P.R. China.
Exp Ther Med. 2018 Apr;15(4):3639-3649. doi: 10.3892/etm.2018.5852. Epub 2018 Feb 8.
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 (10, 10 or 10 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.
转化生长因子β1（TGF-β1）在调节17型辅助性T细胞（Th17）和调节性T细胞（Tregs）的平衡中起关键作用，这两种细胞均参与炎症性肠病的发病机制，而局部TGF-β1在此过程中的功能仍有待充分阐明。本研究调查了不同局部TGF-β1水平对2,4,6-三硝基苯磺酸（TNBS）诱导的结肠炎小鼠中Treg/Th17平衡及地塞米松疗效的影响。通过灌肠给予高、中、低剂量表达TGF-β1的腺病毒（分别为10、10或10 pfu，分别记为AdTGF-1、AdTGF-2和AdTGF-3），使结肠组织达到不同的TGF-β1水平。地塞米松进一步减轻了接受AdTGF-1和AdTGF-2的TNBS小鼠的结肠损伤和髓过氧化物酶活性。给予AdTGF-1时，地塞米松通过减少干扰素（IFN）-γ和增加白细胞介素（IL）-10的产生增强了其作用。在接受AdTGF-2的TNBS小鼠中，地塞米松治疗显著抑制了IFN-γ、肿瘤坏死因子-α、IL-6、IL-17和IL-23的增加。与较低剂量相比，AdTGF-3对TNBS小鼠细胞因子产生的调节作用相反，且不受地塞米松治疗的影响。在肠系膜淋巴结中，AdTGF-1可防止TNBS诱导的Tregs和IL-10减少，并可能增加地塞米松的疗效。此外，地塞米松进一步降低了接受腺病毒TGF-β1的TNBS小鼠中活化的半胱天冬酶3水平，尤其是在AdTGF-1组。给予TNBS处理小鼠低剂量的TGF-β1可显著抑制p38丝裂原活化蛋白激酶/c-Jun氨基末端激酶/c-Jun途径的激活，地塞米松可进一步降低该途径的激活。本研究提供了证据表明，地塞米松的治疗效果可能取决于TNBS诱导的结肠炎中局部TGF-β1的水平，并且可能至少部分通过促进Tregs的分化从而改变促炎和抗炎细胞因子的平衡来介导。
