Poster Presentation 6th Australian Health and Medical Research Congress 2012


Cecilia Prele 1 , AT Handoko 1 , RJ J O'Donoghue 2 , HL Lau 1 , AM Green 1 , GJ Laurent 3 4 , RJ McAnulty 4 , GP Anderson 5 , DA Knight 6 , MR Ernst* 2 , SE Mutsaers* 1
  1. Lung Institute of Western Australia, Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University Of Western Australia , Perth, Australia
  2. Walter and Eliza Hall Institute, Melbourne, Australia
  3. Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University Of Western Australia , Perth, Australia
  4. Centre for Respiratory Research, University College London, London, UK
  5. University of Melbourne, Melbourne, Australia
  6. James Hogg iCapture Centre for Cardiovascular and Pulmonary Research, Vancouver, Canada

We have examined bleomycin-induced fibrosis in mice with different capacities to activate downstream signalling through the gp130-mediated Erk1/2 and Stat1/3 pathways. We observed increased collagen deposition and fibrosis with exaggerated gp130-STAT3 signalling in gp130757F mice when compared to wild type and gp130757F;Stat3+/- mice demonstrating that STAT3 signalling is fundamental to the development of lung fibrosis (O’Donoghue, EMBO Mol Med 2012). We hypothesise that pulmonary fibrosis is mediated by interleukin (IL)-6 family cytokine-induced STAT3 signalling. The aim of the current study was to examine the relative roles of IL-6 and IL-11 in the development of bleomycin-induced pulmonary fibrosis. Bleomycin or saline was administered intranasally to individual and combined IL-6 and IL-11 α-receptor knockout mice IL-6-/-, IL-11αR-/-, IL-6-/-;IL-11αR-/-. In addition we examined the fibrotic response in IL-6 and IL-11 α-receptor knockout mice crossed onto a gp130757F background,  gp130757F;IL-6-/- and gp130757F;IL-11αR-/-. Collagen production and fibrosis was examined by histology and HPLC in lung tissue 30 days post treatment. Total and phosphorylated STAT3 levels were assessed by western blot. Genetic ablation of IL-6 but not IL-11αR significantly reduced collagen production and fibrosis in bleomycin-treated IL-6-/- and IL-11αR-/-mice respectively. Interestingly, ablation of IL-6 in IL-6-/-;IL-11αR-/- mice did not protect from fibrosis. However, knocking out IL-6 and IL-11R in gp130757F mice with exaggerated gp130-STAT signalling significantly reduced fibrosis in bleomycin-treated gp130757F;IL-6-/- and gp130757F;IL-11αR-/- mice. In conclusion, these data indicate that IL-6 plays a significant role in bleomycin-induced pulmonary fibrosis but IL-11 only plays a role when there is an exaggerated STAT response, suggesting that both IL-6 and IL-11 contribute to STAT-mediated fibrosis in vivo.