Toll-like receptor 4 signaling inhibits malignant pleural effusion by altering Th1/Th17 responses.
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.
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.
Qian-Qian
QQ
Xu
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Qiong
Q
Zhou
Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Li-Li
LL
Xu
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hua
H
Lin
Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Xiao-Juan
XJ
Wang
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Wan-Li
WL
Ma
Center of Medical Research, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Kan
K
Zhai
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Center of Medical Research, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Zhao-Hui
ZH
Tong
Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
Yunchao
Y
Su
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.|Center of Medical Research, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Huan-Zhong
HZ
Shi
D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D016066:Pleural Effusion, Malignant / Q000276:immunology* / Q000473:pathology; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D050791:STAT Transcription Factors; D051197:Toll-Like Receptor 4
Th1 cells; Th17 cells; malignant pleural effusion; toll-like receptor 4