WISP1 mediates IL-6-dependent proliferation in primary human lung fibroblasts
S Klee1,2, M Lehmann1,2, D E Wagner1,2
1Comprehensive Pneumology Center, Helmholtz Zentrum München, Munich, Germany.
Scientific Reports
|February 13, 2016
Summary
Wnt1-inducible signaling protein 1 (WISP1) drives fibroblast proliferation in pulmonary fibrosis by increasing interleukin-6 (IL-6) production. This pathway, regulated by TGFβ1 and TNFα, is a potential therapeutic target for idiopathic pulmonary fibrosis (IPF).
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Molecular Biology
Background:
- Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease marked by fibroblast activation and extracellular matrix deposition.
- Wnt1-inducible signaling protein 1 (WISP1) plays a role in the disrupted communication between epithelial and mesenchymal cells in fibrosis.
- Understanding WISP1's regulation and function in lung fibroblasts is crucial for developing IPF therapies.
Purpose of the Study:
- To investigate the regulation of WISP1 by key profibrotic factors in primary human lung fibroblasts (phLFs).
- To elucidate the role of WISP1 in mediating the effects of TGFβ1 and TNFα on fibroblast function, including IL-6 production and proliferation.
- To assess the conservation of these mechanisms in IPF patient-derived fibroblasts.
Main Methods:
- Utilized a luciferase reporter system to confirm direct upregulation of WISP1 by TGFβ1 and TNFα.
- Employed quantitative PCR (qPCR) and ELISA to measure WISP1 mRNA and protein secretion levels.
- Used siRNA-mediated WISP1 knockdown and antibody neutralization to assess WISP1's functional impact on fibroblast proliferation and IL-6 induction.
Main Results:
- WISP1 expression is directly upregulated by Transforming growth factor β1 (TGFβ1) and Tumor necrosis factor α (TNFα) in phLFs in a time- and dose-dependent manner.
- WISP1 is essential for TGFβ1- and TNFα-induced interleukin-6 (IL-6) production, a mechanism observed in IPF fibroblasts.
- Downregulation of WISP1 significantly reduced fibroblast proliferation, an effect partially rescued by IL-6, indicating WISP1-IL-6 axis involvement.
Conclusions:
- WISP1 acts as a key mediator linking profibrotic signals (TGFβ1, TNFα) to fibroblast activation and proliferation.
- The WISP1-induced IL-6 pathway contributes significantly to the pro-proliferative phenotype of lung fibroblasts in fibrosis.
- Targeting the WISP1-IL-6 axis presents a promising therapeutic strategy for idiopathic pulmonary fibrosis.
