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 r... More
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.
