title: WISP1 mediates IL-6-dependent proliferation in primary human lung fibroblasts.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. IPF is characterized by epithelial cell injury and reprogramming, increases in (myo)fibroblasts, and altered deposition of extracellular matrix. The Wnt1-inducible signaling protein 1 (WISP1) is involved in impaired epithelial-mesenchymal crosstalk in pulmonary fibrosis. Here, we aimed to further investigate WISP1 regulation and function in primary human lung fibroblasts (phLFs). We demonstrate that WISP1 is directly upregulated by Transforming growth factor β1 (TGFβ1) and Tumor necrosis factor α (TNFα) in phLFs, using a luciferase-based reporter system. WISP1 mRNA and protein secretion increased in a time- and concentration-dependent manner by TGFβ1 and TNFα in phLFs, as analysed by qPCR and ELISA, respectively. Notably, WISP1 is required for TGFβ1- and TNFα-dependent induction of interleukin 6 (IL-6), a mechanism that is conserved in IPF phLFs. The siRNA-mediated WISP1 knockdown led to a significant IL-6 reduction after TGFβ1 or TNFα stimulation. Furthermore, siRNA-mediated downregulation or antibody-mediated neutralization of WISP1 reduced phLFs proliferation, a process that was in part rescued by IL-6. Taken together, these results strongly indicate that WISP1-induced IL-6 expression contributes to the pro-proliferative effect on fibroblasts, which is likely orchestrated by a variety of profibrotic mediators, including Wnts, TGFβ1 and TNFα.
authors: Comprehensive Pneumology Center, Helmholtz Zentrum München, Munich, Germany.|Member of the Ludwig-Maximilians-Universität, University Hospital Grosshadern and the German Center of Lung Research (DZL), Nußbaumstraße 20, 80336 Munich, Germany.
authors: S
authors: S
authors: Klee
authors: Comprehensive Pneumology Center, Helmholtz Zentrum München, Munich, Germany.|Member of the Ludwig-Maximilians-Universität, University Hospital Grosshadern and the German Center of Lung Research (DZL), Nußbaumstraße 20, 80336 Munich, Germany.
authors: M
authors: M
authors: Lehmann
authors: Comprehensive Pneumology Center, Helmholtz Zentrum München, Munich, Germany.|Member of the Ludwig-Maximilians-Universität, University Hospital Grosshadern and the German Center of Lung Research (DZL), Nußbaumstraße 20, 80336 Munich, Germany.
authors: D E
authors: DE
authors: Wagner
authors: Comprehensive Pneumology Center, Helmholtz Zentrum München, Munich, Germany.|Member of the Ludwig-Maximilians-Universität, University Hospital Grosshadern and the German Center of Lung Research (DZL), Nußbaumstraße 20, 80336 Munich, Germany.
authors: H A
authors: HA
authors: Baarsma
authors: Comprehensive Pneumology Center, Helmholtz Zentrum München, Munich, Germany.|Member of the Ludwig-Maximilians-Universität, University Hospital Grosshadern and the German Center of Lung Research (DZL), Nußbaumstraße 20, 80336 Munich, Germany.
authors: M
authors: M
authors: Königshoff
mesh_terms: D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008168:Lung / Q000166:cytology*; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha