Abstract
Introduction: Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with poor prognosis and limited therapeutic options. IPF is characterized by alveolar epithelial type II (ATII) cell dysfunction, enhanced (myo)fibroblast activation and extracellular matrix deposition. Recently, we have shown that the Wnt-inducible signaling protein (WISP) 1 is upregulated in IPF and we identified WISP1 as a key regulator of experimental pulmonary fibrosis. The regulatory mechanisms involved in the induction of WISP1 expression, however, are poorly understood. In this study, we aim to investigate the regulation of WISP1 expression in healthy and fibrotic lung cells. Results: In silico promoter studies of WISP1 revealed several binding sites for various signaling pathways associated with pulmonary fibrosis, including canonical Wnt-, TGFβ- and Sonic Hedgehog signaling (TCF/LEF, Smad and GLI binding sites). Luciferase-based analysis of specific WISP1-promoter constructs confirmed these data. Moreover, stimulation of human primary fibroblasts (phF) and murine ATII-like cells with TGFβ led to an induction of WISP1 mRNA (fold change: 1.55±0.22 and 0.88±0.14, respectively). Furthermore, TGFβ treatment induced WISP1in a time- and dose-dependent manner in phF on transcript and protein level. Attenuation of TGFβ signaling by using the ALK4/5/7 inhibitor SB431542 resulted in reduced levels of WISP1. Additionally, WISP1 was upregulated in phF by Wnt3a- and TNFα treatment. Conclusion: WISP1 expression is regulated by several profibrotic growth factors. TGFβ induced WISP1 through canonical signaling via ALK4/5/7. WISP1 thus represents a potential downstream mediator for therapeutic intervention in pulmonary fibrosis.
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