Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and has one of the poorest prognosis. However, the molecular mechanisms underlying IPF progression remain largely unknown. In this study, we determined that IL-24, an IL-20 subfamily cytokine member, was increased both in the serum of IPF patients and the bronchoalveolar lavage fluid (BALF) of mice following bleomycin (BLM)-induced pulmonary fibrosis. As a result, IL-24 deficiency protected mice from BLM-induced lung injury and fibrosis. Specifically, loss of IL-24 significantly attenuated transforming growth factor β1 (TGF-β1) production and reduced M2 macrophage infiltration in the lung of BLM-induced mice. Mechanistically, IL-24 alone did not show a perceptible impact on the induction of M2 macrophages, but it synergized with IL-4 to promote M2 program in macrophages. IL-24 suppressed IL-4-induced expression of suppressor of cytokine signaling 1 (SOCS1) and SOCS3, through which it enhanced signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma (STAT6/PPARγ) signaling, thereby promoting IL-4-induced production of M2 macrophages. Collectively, our data support that IL-24 synergizes with IL-4 to promote macrophage M2 program contributing to the development of pulmonary fibrosis.

特发性肺纤维化（IPF）是特发性间质性肺炎最常见的类型，也是预后最差的类型之一。然而，IPF 进展的分子机制仍然很大程度上未知。在这项研究中，我们确定IL-24（IL-20亚家族细胞因子成员）在IPF患者的血清和博莱霉素（BLM）诱导的肺纤维化后小鼠的支气管肺泡灌洗液（BALF）中均增加。结果，IL-24缺乏可以保护小鼠免受 BLM 诱导的肺损伤和纤维化。具体而言，IL-24的缺失显着减弱了 BLM 诱导小鼠肺中转化生长因子 β1 (TGF-β1) 的产生，并减少了 M2 巨噬细胞的浸润。从机制上讲，单独的IL-24对M2巨噬细胞的诱导没有显示出明显的影响，但它与IL-4协同促进巨噬细胞中的M2程序。IL-24 抑制 IL-4 诱导的细胞因子信号传导抑制因子 1 (SOCS1) 和 SOCS3 的表达，从而增强信号转导子和转录激活因子 6/过氧化物酶体增殖物激活受体 γ (STAT6/PPARγ) 信号传导，从而促进 IL -4诱导M2巨噬细胞的产生。总的来说，我们的数据支持 IL-24 与 IL-4 协同促进巨噬细胞 M2 程序，从而导致肺纤维化的发展。