Interleukin-6 induces Gr-1+CD11b+ myeloid cells to suppress CD8+ T cell-mediated liver injury in mice.
Interleukin-6 induces Gr-1+CD11b+ myeloid cells to suppress CD8+ T cell-mediated liver injury in mice.
复制标题
白介素-6诱导GR-1+ CD11b+髓样细胞抑制小鼠CD8+ T细胞介导的肝损伤。
DOI：
10.1371/journal.pone.0017631
复制
发表时间：
2011-03-04
期刊：
影响因子：
3.7
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Cheng L;Wang J;Li X;Xing Q;Du P;Su L;Wang S
T淋巴细胞上针对CD 137（4-1BB）的激动剂抗体用于增强宿主抗肿瘤免疫力，但在临床试验期间通常会导致治疗小鼠或患者严重的肝损伤。白细胞介素-6（IL-6）对肝细胞死亡具有保护作用，但由于缺乏相关的动物模型，IL-6对慢性T细胞诱导的肝病的保护作用尚不明确。我们的目的是确定IL-6在小鼠中由CD 137激动性mAb（克隆2A）诱导的CD 8 + T细胞介导的肝损伤中的作用。我们在用2A或对照mAb处理的小鼠中通过流体动力学基因递送在肝脏中表达IL-6，并研究IL-6处理如何影响宿主免疫和T细胞介导的肝损伤。我们发现，异位IL-6在肝脏表达升高肝内白细胞浸润，但防止CD 8 + T细胞介导的肝损伤。在IL-6处理的小鼠中，肝脏中的CD 8 + T细胞增殖和IFN-γ表达受到抑制。我们发现IL-6增加了肝脏和脾脏中Gr-1+ CD 11b+髓源性抑制细胞（MDSC）的积累。这些MDSC具有抑制T细胞增殖和活化的能力。最后，我们发现MDSC对于IL-6介导的抗CD 137 mAb诱导的肝损伤的保护是足够的和必需的。我们的结论是，IL-6诱导肝脏中的Gr-1+ CD 11b + MDSCs抑制T细胞介导的肝损伤。这些发现已经确定了IL-6保护肝脏免受CD 8 + T细胞介导的损伤的新机制。
Agonist antibodies against CD137 (4–1BB) on T lymphocytes are used to increase host anti-tumor immunity, but often leading to severe liver injury in treated mice or in patients during clinical trials. Interleukin-6 (IL-6) has been reported to protect hepatocyte death, but the role of IL-6 in protecting chronic T cell-induced liver diseases is not clearly defined due to lack of relevant animal models. We aimed to define the role of IL-6 in CD8+ T cell-mediated liver injury induced by a CD137 agonistic mAb (clone 2A) in mice. We expressed IL-6 in the liver by hydrodynamic gene delivery in mice treated with 2A or control mAb and studied how IL-6 treatment affected host immunity and T cell-mediated liver injury. We found that ectopic IL-6 expression in the liver elevated intrahepatic leukocyte infiltration but prevented CD8+ T cell-mediated liver injury. In IL-6 treated mice, CD8+ T cells proliferation and IFN-γ expression were inhibited in the liver. We discovered that IL-6 increased accumulation of Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) in the liver and spleen. These MDSCs had the ability to inhibit T cells proliferation and activation. Finally, we showed that the MDSCs were sufficient and essential for IL-6-mediated protection of anti-CD137 mAb-induced liver injury. We concluded that IL-6 induced Gr-1+CD11b+ MDSCs in the liver to inhibit T cell-mediated liver injury. The findings have defined a novel mechanism of IL-6 in protecting liver from CD8+ T cell-mediated injury.
登录
查看更多内容
DOI：
10.1084/jem.20091474
发表时间：
2010-07-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sander LE;Sackett SD;Dierssen U;Beraza N;Linke RP;Müller M;Blander JM;Tacke F;Trautwein C
通讯作者：
Trautwein C
DOI：
10.1084/jem.179.5.1529
发表时间：
1994-05-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Mizuhara H;O'Neill E;Seki N;Ogawa T;Kusunoki C;Otsuka K;Satoh S;Niwa M;Senoh H;Fujiwara H
通讯作者：
Fujiwara H
DOI：
10.1016/s0006-291x(03)00572-2
发表时间：
2003-04-25
影响因子：
3.1
作者：
Masubachi, Y;Bourdi, M;Pohl, LR
通讯作者：
Pohl, LR
影响因子：
11.2
作者：
Bunt, Stephanie K.;Yang, Linglin;Ostrand-Rosenberg, Suzanne
通讯作者：
Ostrand-Rosenberg, Suzanne
影响因子：
8
作者：
Hong, F;Kim, WH;Gao, B
通讯作者：
Gao, B