2. Academic Validation
  3. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis

Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis

  • Sci Transl Med. 2019 Sep 25;11(511):eaaw1237. doi: 10.1126/scitranslmed.aaw1237.
Benjamin Ng 1 2,  Jinrui Dong 2,  Giuseppe D'Agostino 2,  Sivakumar Viswanathan 2,  Anissa A Widjaja 2,  Wei-Wen Lim 1 2,  Nicole S J Ko 2,  Jessie Tan 1 2,  Sonia P Chothani 2,  Benjamin Huang 2,  Chen Xie 1,  Chee Jian Pua 1,  Ann-Marie Chacko 2,  Nuno Guimarães-Camboa 3 4 5,  Sylvia M Evans 5 6 7,  Adam J Byrne 8,  Toby M Maher 8 9,  Jiurong Liang 10 11,  Dianhua Jiang 10 11,  Paul W Noble 10 11,  Sebastian Schafer 1 2,  Stuart A Cook 12 2 13 14
Affiliations

Affiliations

  • 1 National Heart Centre Singapore, 169609 Singapore, Singapore.
  • 2 Duke-National University of Singapore Medical School, 169857 Singapore, Singapore.
  • 3 Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt 60590, Germany.
  • 4 German Center for Cardiovascular Research DZHK, Berlin 10785, Germany.
  • 5 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 6 Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 7 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  • 8 Fibrosis Research Group, Inflammation, Repair and Development Section, National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK.
  • 9 NIHR Biomedical Research Unit, Royal Brompton Hospital, London SW7 2AZ, UK.
  • 10 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 11 Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 12 National Heart Centre Singapore, 169609 Singapore, Singapore. stuart.cook@duke-nus.edu.sg.
  • 13 National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
  • 14 MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK.
PMID: 31554736 DOI: 10.1126/scitranslmed.aaw1237
Abstract

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 (IL11) 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 (Il11ra1)-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.

Figures
Products