title: Regulation of TGF-β storage and activation in the human idiopathic pulmonary fibrosis lung.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Pulmonary Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. outi.lepparanta@helsinki.fi
authors.forename: Outi
authors.initials: O
authors.lastname: Leppäranta
authors.forename: Carla
authors.initials: C
authors.lastname: Sens
authors.forename: Kaisa
authors.initials: K
authors.lastname: Salmenkivi
authors.forename: Vuokko L
authors.initials: VL
authors.lastname: Kinnula
authors.forename: Jorma
authors.initials: J
authors.lastname: Keski-Oja
authors.forename: Marjukka
authors.initials: M
authors.lastname: Myllärniemi
authors.forename: Katri
authors.initials: K
authors.lastname: Koli
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D005353:Fibronectins; D016023:Integrins; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins; D012333:RNA, Messenger; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; C000605722:FBN1 protein, human; D054392:Adipokines; C000605723:FBN2 protein, human; C497782:SMAD2 protein, human; C508960:TGFB1 protein, human