Roh Yoon Seok, Park Surim, Lim Chae Woong, Kim Bumseok
Laboratory of Pathology, College of Veterinary Medicine (BK21 Plus Program), Chonbuk National University, Jeonju, 561-756, South Korea.
Dig Dis Sci. 2015 Jul;60(7):2009-18. doi: 10.1007/s10620-014-3438-2. Epub 2014 Nov 22.
Accumulating evidence suggests that Foxp3+ regulatory T (Treg) cells act as inhibitory mediators of inflammation; however, the in vivo mechanism underlying this protection remains elusive in liver diseases.
To clarify the in vivo role of Foxp3+ Treg cells in liver fibrosis, we used the DEREG mouse, which expresses the diphtheria toxin receptor under control of the Foxp3 promoter, allowing for specific deletion of Foxp3+ Treg cells.
Bile duct ligation-induced liver injury and fibrosis were assessed by histopathology, fibrogenic gene expression, and measurement of cytokine and chemokine levels.
Depletion of Foxp3+ Treg cells enhanced Th17 cell response as demonstrated by the increase of IL-17+ cells and related gene expressions including Il17f, Il17ra, and Rorgt in the fibrotic livers of DEREG mice. Of note, infiltration of CD8+ T cells and Cd8 gene expression was significantly increased in the livers of DEREG mice. Consistent with increased IL-17+ and CD8+ T cell responses, DEREG mice generated higher levels of inflammatory cytokines (TNF-α, IL-6, and IL-12p70) and chemokines (MCP-1, MIP-1α, and RANTES). These results were concordant with severity of liver fibrosis and hepatic enzyme levels (ALT and ALP).
The present findings demonstrate that Foxp3+ Treg cells inhibit the profibrogenic inflammatory milieu through suppression of pro-fibrogenic CD8+ and IL-17+ T cells.
越来越多的证据表明，Foxp3 + 调节性T（Treg）细胞作为炎症的抑制介质；然而，在肝脏疾病中，这种保护作用的体内机制仍不清楚。
为了阐明Foxp3 + Treg细胞在肝纤维化中的体内作用，我们使用了DEREG小鼠，该小鼠在Foxp3启动子的控制下表达白喉毒素受体，从而允许特异性删除Foxp3 + Treg细胞。
通过组织病理学、纤维化相关基因表达以及细胞因子和趋化因子水平的测定，评估胆管结扎诱导的肝损伤和纤维化。
Foxp3 + Treg细胞的缺失增强了Th17细胞反应，DEREG小鼠纤维化肝脏中IL-17 + 细胞以及包括Il17f、Il17ra和Rorgt在内的相关基因表达增加证明了这一点。值得注意的是，DEREG小鼠肝脏中CD8 + T细胞浸润和Cd8基因表达显著增加。与IL-17 + 和CD8 + T细胞反应增加一致，DEREG小鼠产生了更高水平的炎性细胞因子（TNF-α、IL-6和IL-12p70）和趋化因子（MCP-1、MIP-1α和RANTES）。这些结果与肝纤维化的严重程度和肝酶水平（ALT和ALP）一致。
本研究结果表明，Foxp3 + Treg细胞通过抑制促纤维化的CD8 + 和IL-17 + T细胞来抑制促纤维化的炎症环境。
