Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells
Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells
复制标题
DOI：
10.1152/ajpgi.00329.2010
复制
发表时间：
2011-04-01
影响因子：
4.5
通讯作者：
Kaneko, Kenji
中科院分区：
文献类型：
--
作者：
Sasaoka, Tetsumasa;Ito, Masayuki;Kaneko, Kenji
Sasaoka T，Ito M，Yamashita J，Nakajima K，Tanaka I，Narita M，Hara Y，Hada K，Takahashi M，Ohno Y，Matsuo T，Kaneshiro Y，Tanaka H，Kaneko K.用IL-27治疗通过抑制产生IL-17的T辅助细胞的发育来减轻实验性结肠炎。美国生理学杂志胃肠和肝脏生理学300：G568-G576，2011年。首次发表于2010年12月30日; doi：10.1152/ajpgi.00329.2010.-炎症性肠病（IBD）是一组以炎症和复发性胃肠道疾病为特征的慢性炎症性疾病。最近的研究表明，Th 17细胞是众所周知的慢性炎症的关键介质，在人类和小鼠IBD的发病和发展中起着关键作用。近年来，已经报道了IL-27（其是由EBI 3和p28亚基组成的IL-12相关的异二聚体细胞因子）直接作用于初始T细胞以抑制Th 17细胞的分化。然而，外源性IL-27对IBD的影响尚未得到很好的阐明。为了阐明IL-27治疗对IBD的抑制作用，我们将柔性连接方法应用于EBI 3和p28亚基并产生单链人IL-27（scIL-27）。scIL-27在体外抑制异种小鼠Th 17细胞分化，表明scIL-27也在小鼠免疫系统中起作用。在2，4，6-三硝基苯磺酸（TNBS）诱导的小鼠急性结肠炎模型中，皮下scIL-27治疗以剂量依赖性方式显著改善结肠长度、坏死程度、溃疡和增厚的上皮以及若干病理评分。scIL-27明显抑制炎症结肠中的几种炎性细胞因子，包括IL-17，除了抗炎细胞因子IL-10。来自scIL-27处理的小鼠的肠系膜淋巴结细胞也表现出减少的炎症反应，此外，比PBS处理的小鼠的Th 17细胞群体更低。最后，我们显示了scIL-27对TNBS诱导的结肠炎的治疗功效，即使在建立活动性结肠炎之后。这些结果为IBD提供了新的可能的治疗方法，包括克罗恩病和溃疡性结肠炎等疾病。
Sasaoka T, Ito M, Yamashita J, Nakajima K, Tanaka I, Narita M, Hara Y, Hada K, Takahashi M, Ohno Y, Matsuo T, Kaneshiro Y, Tanaka H, Kaneko K. Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells. Am J Physiol Gastrointest Liver Physiol 300: G568-G576, 2011. First published December 30, 2010; doi: 10.1152/ajpgi.00329.2010.-Inflammatory bowel disease (IBD) represents a group of chronic inflammatory diseases characterized by inflammation and relapsing gastrointestinal disorders. Recent studies have shown that Th17 cells, which are well known as key mediators of chronic inflammation, have a pivotal role in onset and development of IBD in humans and mice, alike. In recent years, it has been reported that IL-27, which is an IL-12-related heterodimeric cytokine consisting of EBI3 and p28 subunits, act directly on naive T cells to suppress the differentiation of Th17 cells. However, effects of exogenous IL-27 on the IBD are not well elucidated. To clarify the suppressive effect of IL-27 treatment on IBD, we applied the flexible linking method to EBI3 and p28 subunits and generated a single-chain human IL-27 (scIL-27). scIL-27 inhibited xenogenic mouse Th17 cell differentiation in vitro, indicating that scIL-27 also acts in mouse immune systems. In a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse acute colitis model, subcutaneous scIL-27 treatment significantly improved the colon length, extent of necrosis, and ulceration and thickened epithelium and several pathological scores in a dose-dependent manner. scIL-27 clearly suppressed several inflammatory cytokines, including IL-17, in inflamed colon, except for anti-inflammatory cytokine IL-10. The mesenteric lymph node cells from scIL-27-treated mice also exhibited a reduced inflammatory response and, furthermore, a lower population of Th17 cells than those of PBS-treated mice. Finally, we showed the therapeutic efficacy of scIL-27 on TNBS-induced colitis even after active colitis was established. These results suggest new possible therapeutic approaches for IBD, including disorders such as Crohn's disease and ulcerative colitis.