IL-6反式訊息傳遞途徑在放射線導致之肺纖維化中所扮演的角色

Abstract

放射線造成之肺部纖維化是胸腔接受放射治療後產生的長期副作用，目前的治療方法仍然屈指可數，這些肺纖維化不只阻礙了後續治療更會導致威脅生命的情況，放射線肺纖維化的機制至今沒有被我們清楚的理解。但是我們知道血清中介白素-6(IL-6)的濃度是一個指標可以呈現疾病的嚴重度，而抑制小鼠的IL-6也確實減輕了肺纖維化的強度。然而，我們並不知道這樣子的原因是由於IL-6傳統途徑經由細胞膜上的接受器mIL-6還是經由反式訊息傳遞途徑(trans-signaling pathway)的sIL-6。在這篇研究中，我們探討IL-6在放射線肺纖維化過程中所扮演的角色。我們證明了IL-6反式訊息傳遞途徑在小鼠的肺纖維化過程中有活化，利用小鼠放射肺纖維化的動物模式，我們證明相較於一般C57BL/6小鼠，sgp130Tg小鼠可以有效減輕放射肺纖維化的程度並降低死亡率，而這個現象又與sgp130Tg小鼠的肺部上皮間質轉化(Epithelial-Mesenchymal-Transition)有關。在體外，IL-6反式訊息傳遞途徑會刺激STAT3的磷酸化並壓制E-cadherin在肺上皮細胞的表現，進一步影響肺纖維化的嚴重度。總而言之，這些証據是第一次有人証實IL-6的反式訊息傳遞途徑在放射線肺纖維化中扮演重要的角色，更進一步指出選擇性地抑制IL-6反式訊息傳遞途徑可能是另一種治療放射線肺纖維化的新方向

Radiation-induced pulmonary fibrosis (RIPF) is a late side effect of thoracic radiotherapy with few effective treatments available. Fibrosis progression not only impedes further radiation treatment but also brings life-threatening condition. The pathophysiology of RIPF is not well understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Inhibition of IL-6 results in attenuation of pulmonary fibrosis in mice. However, it is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6Rα(mIL-6Rα), or trans-signaling, mediated by soluble IL-6Rα (sIL-6Rα). Here, we assessed the role of sIL-6Rα in RIPF. We demonstrated activation of IL-6 trans-signaling in mice during the onset and progression of lung fibrosis. Using a mouse model of RIPF, we demonstrated that sgp130Tg mice had a remarkable reduction in RIPF and a lower death rate compared with wild type C57BL/6 mice. This observation was associated with an attenuation of pulmonary epithelial-to-mesenchymal transition (EMT) in sgp130Tg mice. In vitro, IL-6 trans-signaling stimulated phosphorylation of STAT3 and suppressed of E-cadherin expression in lung epithelial cells, effects relevant in the progression of pulmonary fibrosis. Taken together, these results provide the first evidence that IL-6 trans-signaling mediated signaling cascade plays an essential role in the pathogenesis of RIPF, and suggest that selective inhibition of IL-6 trans-signaling may be a novel therapeutic strategy for the management of RIPF.