National Heart Centre Singapore, 169609 Singapore, Singapore.
Duke-National University of Singapore Medical School, 169857 Singapore, Singapore.
Sci Transl Med. 2019 Sep 25;11(511). doi: 10.1126/scitranslmed.aaw1237.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here, we show that interleukin-11 () is up-regulated in the lung of patients with IPF, associated with disease severity, and IL-11 is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle-positive (ACTA2), collagen-secreting myofibroblasts in an extracellular signal-regulated kinase (ERK)-dependent, posttranscriptional manner. In mice, fibroblast-specific transgenic expression or administration of murine IL-11 induces lung myofibroblasts and causes lung fibrosis. IL-11 receptor subunit alpha-1 ()-deleted mice, whose lung fibroblasts are unresponsive to profibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11-neutralizing antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment diminished lung inflammation and reversed lung fibrosis while inhibiting ERK and SMAD activation in mice. These data prioritize IL-11 as a drug target for lung fibrosis and IPF.
特发性肺纤维化（IPF）是一种进行性肺纤维化疾病，其中侵袭性肺肌成纤维细胞分泌胶原并破坏肺完整性。在这里，我们表明白细胞介素 11（IL-11）在 IPF 患者的肺部上调，与疾病严重程度相关，并且 IL-11 由 IPF 成纤维细胞分泌。在体外，IL-11 以细胞外信号调节激酶（ERK）依赖性、转录后方式刺激肺成纤维细胞成为侵袭性肌动蛋白 alpha 2、平滑肌阳性（ACTA2）、分泌胶原蛋白的肌成纤维细胞。在小鼠中，成纤维细胞特异性转基因表达或施用鼠 IL-11 诱导肺肌成纤维细胞并引起肺纤维化。IL-11 受体亚基 alpha-1（）缺失小鼠，其肺成纤维细胞对促纤维化刺激无反应，在博来霉素诱导的肺纤维化小鼠模型中免受纤维化。我们生成了一种 IL-11 中和抗体，该抗体可阻断多种刺激物下游的肺成纤维细胞激活并逆转肌成纤维细胞激活。在治疗研究中，抗 IL-11 治疗可减轻肺部炎症并逆转肺部纤维化，同时抑制 ERK 和 SMAD 在小鼠中的激活。这些数据将 IL-11 确定为肺纤维化和 IPF 的药物靶标。
