Regulation of TGF-β storage and activation in the human idiopathic pulmonary fibrosis lung

• Published in: Cell and tissue research 2012-06, Vol.348 (3), p.491-503
• Main Authors: Leppäranta, Outi, Sens, Carla, Salmenkivi, Kaisa, Kinnula, Vuokko L, Keski-Oja, Jorma, Myllärniemi, Marjukka, Koli, Katri
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biomedical and Life Sciences; Biomedicine; blood vessels; Bone morphogenetic proteins; Case-Control Studies; Cells, Cultured; Down-Regulation - genetics; epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; extracellular matrix; Fibrillin-1; Fibrillin-2; Fibrillins; fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Fibronectins; Fibronectins - metabolism; fibrosis; gene expression; gene expression regulation; genes; Human Genetics; Humans; Idiopathic Pulmonary Fibrosis - metabolism; Integrins; Integrins - metabolism; Latent TGF-beta Binding Proteins - genetics; Latent TGF-beta Binding Proteins - metabolism; Lung - metabolism; Lung - pathology; lungs; Microfilament Proteins - metabolism; Middle Aged; Molecular Medicine; pathogenesis; Phosphorylation; Protein binding; Protein Transport; Proteomics; Pulmonary fibrosis; Regular Article; Respiratory tract diseases; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Smad2 Protein - metabolism; small interfering RNA; transforming growth factor beta; Transforming Growth Factor beta1 - metabolism; Transforming growth factors; Up-Regulation - genetics
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-012-1385-9

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown cause. The pathogenesis of the disease is characterized by fibroblast accumulation and excessive transforming growth factor-β (TGF-β) activation. Although TGF-β activation is a complex process involving various protein interactions, little is known of the specific routes of TGF-β storage and activation in human lung. Here, we have systematically analyzed the expression of specific proteins involved in extracellular matrix targeting and activation of TGF-β. Latent TGF-β-binding protein (LTBP)-1 was found to be significantly upregulated in IPF patient lungs. LTBP-1 expression was especially high in the fibroblastic foci, in which P-Smad2 immunoreactivity, indicative of TGF-β signaling activity, was less prominent. In cultured primary lung fibroblasts and epithelial cells, short-interfering-RNA-mediated downregulation of LTBP-1 resulted in either increased or decreased TGF-β signaling activity, respectively, suggesting that LTBP-1-mediated TGF-β activation is dependent on the cellular context in the lung. Furthermore, LTBP-1 was shown to colocalize with fibronectin, fibrillin-1 and fibrillin-2 proteins in the IPF lung. Fibrillin-2, a developmental gene expressed only in blood vessels in normal adult lung, was found specifically upregulated in IPF fibroblastic foci. The TGF-β-activating integrin β8 subunit was expressed at low levels in both control and IPF lungs. Alterations in extracellular matrix composition, such as high levels of the TGF-β storage protein LTBP-1 and the re-appearance of fibrillin-2, probably modulate TGF-β availability and activation in different pulmonary compartments in the fibrotic lung.