Xu Qian-Qian, Zhou Qiong, Xu Li-Li, Lin Hua, Wang Xiao-Juan, Ma Wan-Li, Zhai Kan, Tong Zhao-Hui, Su Yunchao, Shi Huan-Zhong
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Cell Biol Int. 2015 Oct;39(10):1120-30. doi: 10.1002/cbin.10485. Epub 2015 Jun 24.
Toll-like receptor 4 (TLR4) is involved in multiple malignancies; however, the role of TLR4 in the pathogenesis of malignant pleural effusion (MPE) remains unknown. The objectives of this study were to explore the impact of TLR4 signaling on the development of MPE in a murine model and to define the underline mechanisms by which TLR works. Development of MPE as well as proliferation and angiogenesis of pleural tumor were determined in TLR4(-/-) and wild type mice. Differentiation of Th1 and Th17 cells as well as their signal transductions was explored. The effects of TLR4 signaling on survival of mice bearing MPE were also investigated. Compared with wild type mice, Th1 cells were augmented, and Th17 cells were suppressed in MPE from TLR4(-/-) mice. The in vitro experiments showed that TLR4 deficiency promoted Th1 cell differentiation via enhancing STAT1 pathway and inhibited Th17 cell differentiation via suppressing STAT3 pathway. TLR4 deficiency promoted MPE formation and, thus, accelerated the death of mice bearing MPE, whereas intraperitoneal injection of anti-IFN-γ mAb or recombinant mouse IL-17 protein into TLR4(-/-) mice was associated with improved survival. Our data provides the first definitive evidence of a role for TLR4 signaling in protective immunity in the development of MPE. Our findings also demonstrate that TLR4 deficiency promotes MPE formation and accelerates mouse death by enhancing Th1 and suppressing Th17 response.
Toll样受体4（TLR4）与多种恶性肿瘤相关；然而，TLR4在恶性胸腔积液（MPE）发病机制中的作用尚不清楚。本研究的目的是探讨TLR4信号在小鼠模型中对MPE发生发展的影响，并确定TLR发挥作用的潜在机制。在TLR4基因敲除（-/-）小鼠和野生型小鼠中测定MPE的发生以及胸膜肿瘤的增殖和血管生成。探讨Th1和Th17细胞的分化及其信号转导。还研究了TLR4信号对荷MPE小鼠生存的影响。与野生型小鼠相比，TLR4（-/-）小鼠的MPE中Th1细胞增加，Th17细胞受到抑制。体外实验表明，TLR4缺陷通过增强STAT1途径促进Th1细胞分化，并通过抑制STAT3途径抑制Th17细胞分化。TLR4缺陷促进MPE形成，从而加速荷MPE小鼠的死亡，而向TLR4（-/-）小鼠腹腔注射抗IFN-γ单克隆抗体或重组小鼠IL-17蛋白可改善生存。我们的数据首次明确证明了TLR4信号在MPE发生发展中的保护性免疫作用。我们的研究结果还表明，TLR4缺陷通过增强Th1反应和抑制Th17反应促进MPE形成并加速小鼠死亡。
