Toll-Like Receptor4Signaling Inhibits Malignant Pleural Effusion By Altering Th1/Th17Responses

Rationale:Toll-like receptor4(TLR4) is involved in multiple malignancies; however, the role of TLR4in the pathogenesis of malignant pleural effusion (MPE) remains unknown.Objectives:To explore the impact of TLR4signaling on the development of MPE in a murine model, and to define the underline mechanisms by which TLR works.Methods:Development of MPE as well as proliferation and angiogenesis of pleural tumor were determined in TLR4-/-and wild type mice. Differentiation of Thl and Th17cells as well as their signal transductions was explored. The effects of TLR4signaling on survival of mice bearing MPE were also investigated.Measurements and Main Results:Compared with wild type mice, Thl cells were augmented and Th17cells were suppressed in MPE from TLR4-/-mice. The in vitro experiments showed that TLR4deficiency promoted Thl cell differentiation via enhancing STAT1pathway, and inhibited Th17cell differentiation via suppressing STAT3pathway. TLR4deficiency promoted MPE formation by promoting angiogenesis and proliferation activity of pleural tumor, and thus accelerated the death of mice bearing MPE, whereas intraperitoneal injection of anti-IFN-y mAb or recombinant mouse IL-17protein into TLR4-/-mice was associated with improved survival.Conclusions:Our data provide the first definitive evidence of a role for TLR4signaling in protective immunity in the development of MPE. Our findings also demonstrate that TLR4deficiency promotes MPE formation and accelerates mouse death by enhancing Thl and suppressing Th17response.