白介素22通过JAK2/STAT3抑制TGF-βR2表达参与特发性肺纤维化发病机制研究

特发性肺纤维化（IPF）病因和发病机制未明，TGF-β信号通道可通过上皮间充质转换、凋亡、衰老和自噬等多种途径调控肺纤维化发生。白介素22（IL-22）是一种具有多种功能细胞因子，能够通过活化JAK2/STAT3在纤维化和急性肺损伤中发挥保护性作用。前期研究发现，在IPF患者和博来霉素（BLM）诱导小鼠体内IL-22低表达、TGF-βR2高表达，磷酸化JAK2和STAT3表达增加；重组IL-22能够抑制BLM诱导小鼠肺组织TGF-βR2表达和胶原纤维的形成。我们推测，IL-22可以通过进一步激活JAK2/STAT3信号通道，抑制TGF-βR2表达，参与肺纤维化发病。本课题拟采用IL-22R和TGF-βR敲除慢病毒质粒转染原代肺泡Ⅱ型上皮细胞和成纤维细胞培养、基因敲除和BLM诱导肺纤维化小鼠模型，从细胞和动物水平探讨IL-22在IPF发病中作用和分子机制，为寻求IPF治疗新靶点提供理论依据。

The etiology and pathogenesis of idiopathic pulmonary fibrosis (IPF) have not been clearly defined. TGF-β signaling has been established to play an very important role in the pathogenesis of IPF by mediating epithelial mesenchymal transformation (EMT), apoptosis, senescence and autophagy. Interleukin-22 (IL-22) is a multifunctional cytokine and has demonstrated a protective function in fibrosis and acute lung injury via activating JAK2/STAT3 signal. We have shown an inverse relationship between IL-22 and a major TGF-β receptor (i.e. TGF-βR2) in IPF and Bleomycin (BLM) induced mice, where IL-22 expression was decreased and TGF-βR2 and phosphorylated JAK2/STAT3 expression was increased. Furthermore, exogenous IL-22 inhibited TGF-βR2 expression and reduced lung fibrosis in a Bleomycin (BLM) induced mouse model of lung fibrosis, suggesting a causal role of IL-22 in the repression of TGF-β pathway. In the cell culture models of A549 cells and primary fibroblasts, IL-22 was able to activate JAK2/STAT3 and repressed TGF-βR2 as well as TGF-β downstream genes including Collagen-1 and α-smooth muscle agonist protein (α-SMA) significantly. Therefore, we hypothesize that the protective function of IL-22 against IPF is likely mediated by the inhibition of lung fibrosis via JAK2/STAT3/TGF-βR2 axis. To further explore the underlying mechanistic basis through which IL-22 protects against IPF, we proposed to test this hypothesis by primary cell cultures (i.e. primary alveolar type Ⅱ epithelial cells and lung fibroblasts), IL-22R and TGF-βR2 knockout mice and BLM induced mice models of lung fibrosis. The success of this project will establish a foundation for further development of an IL-22 based targeted therapy to treat IPF.