Regulation of TGF-β storage and activation in the human idiopathic pulmonary fibrosis lung
| Autor: | Katri Koli, Outi Leppäranta, Marjukka Myllärniemi, Jorma Keski-Oja, Vuokko L. Kinnula, Kaisa Salmenkivi, Carla Sens |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
Integrins Pathology medicine.medical_specialty Histology Fibrillin-2 Fibrillin-1 Down-Regulation Smad2 Protein Biology Fibrillins Pathology and Forensic Medicine Transforming Growth Factor beta1 Extracellular matrix Idiopathic pulmonary fibrosis Downregulation and upregulation medicine Humans RNA Messenger Phosphorylation Fibroblast Lung Cells Cultured Aged Microfilament Proteins Epithelial Cells Cell Biology Fibroblasts Middle Aged respiratory system Endoglin medicine.disease Idiopathic Pulmonary Fibrosis Fibronectins Up-Regulation respiratory tract diseases Fibronectin Protein Transport medicine.anatomical_structure Latent TGF-beta Binding Proteins Case-Control Studies Cancer research biology.protein Transforming growth factor |
| Zdroj: | Cell and Tissue Research. 348:491-503 |
| ISSN: | 1432-0878 0302-766X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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