The Role of IL-6 trans-signaling pathway in Radiation-induced Pulmonary Fibrosis

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.