Idiopathic pulmonary fibrosis (IPF) is a progressive and grave lung disease and its etiology is insufficiently understood. Defects in TGF-beta signaling and WNT signaling are deemed to be of major relevance to the pathogenetic process of IPF. The LIM protein FHL2 has been shown to modulate TGF-beta signaling and WNT signaling in various cellular contexts. It may also serve as an interface for crosstalk between the two pathways. FHL2 is known to regulate fibrogenesis and to promote fibroblast to myofibroblast transition and epithelial-to-mesenchymal transition (EMT), which are deemed to constitute key events in IPF. FHL2 is often characterized as profibrotic in nature. Nevertheless, it has also been ascribed antifibrotic properties in the bleomycin-mouse-model of IPF. To date, nothing is known about a possible involvement of FHL2 in human IPF.This study examines the expression, localization and function of FHL2 in IPF. Quantitative (q)RT-PCR performed on lung homogenates displayed a 3.25-fold upregulation of FHL2 mRNA levels in IPF lungs compared with controls (transplant donors). Western blot analysis of the same material confirmed a significant upregulation of FHL2 protein in IPF lungs. Using immunohistochemistry, FHL2 was localized to fibroblasts, as well as to bronchial and alveolar epithelial cells in IPF lungs and in healthy lungs. Stimulation of human fibroblasts with TGF-beta resulted in enhanced expression of FHL2 mRNA (3.2 fold) and protein (4.2 fold). Finally, overexpression of FHL2, led to a significant potentiation of Smaddependent TGF-beta signaling in NIH-cells, as assessed by Luciferase assays and phospho Western blots. In conclusion, these results suggest that FHL2 might act as a profibrotic regulator in IPF.
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