scholarly journals MUC16 Is Overexpressed in Idiopathic Pulmonary Fibrosis and Induces Fibrotic Responses Mediated by Transforming Growth Factor-β1 Canonical Pathway

2021 ◽  
Vol 22 (12) ◽  
pp. 6502
Author(s):  
Beatriz Ballester ◽  
Javier Milara ◽  
Paula Montero ◽  
Julio Cortijo
Keyword(s):  
Transforming Growth Factor ◽  
A549 Cells ◽  
Transforming Growth Factor Β1 ◽  
Canonical Pathway ◽  
Lung Fibroblasts ◽  
Alveolar Type ◽  
Type Ii ◽  
Smad3 Phosphorylation ◽  
Smad Binding Element ◽  
Tgf Β1

Several transmembrane mucins have demonstrated that they contribute intracellularly to induce fibrotic processes. The extracellular domain of MUC16 is considered as a biomarker for disease progression and death in IPF patients. However, there is no evidence regarding the signalling capabilities of MUC16 that contribute to IPF development. Here, we demonstrate that MUC16 was overexpressed in the lung tissue of IPF patients (n = 20) compared with healthy subjects (n = 17) and localised in fibroblasts and hyperplastic alveolar type II cells. Repression of MUC16 expression by siRNA-MUC16 transfection inhibited the TGF-β1-induced fibrotic processes such as mesenchymal/ myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as fibroblast proliferation. SiRNA-MUC16 transfection also decreased the TGF-β1-induced SMAD3 phosphorylation, thus inhibiting the Smad Binding Element activation. Immunoprecipitation assays and confocal immunofluorescence showed the formation of a protein complex between MUC16/p-SMAD3 in the cell membrane after TGF-β1 stimulation. This study shows that MUC16 is overexpressed in IPF and collaborates with the TGF-β1 canonical pathway to induce fibrotic processes. Therefore, direct or indirect targeting of MUC16 could be a potential drug target for human IPF.

Regulation of extracellular matrix synthesis by TNF-α and TGF-β1 in type II cells exposed to coal dust

1998 ◽  
Vol 275 (4) ◽  
pp. L637-L644 ◽  
Author(s):  
Yu-Chen Lee ◽  
D. Eugene Rannels
Keyword(s):  
Extracellular Matrix ◽  
Cell Cultures ◽  
Transforming Growth Factor ◽  
Coal Dust ◽  
Transforming Growth Factor Β1 ◽  
Type Ii ◽  
Tnf Α ◽  
Type Ii Cell ◽  
Primary Type ◽  
Tgf Β1

Type II pulmonary epithelial cells respond to anthracite coal dust PSOC 867 with increased synthesis of extracellular matrix (ECM) components. Alveolar macrophages modulate this response by pathways that may involve soluble mediators, including tumor necrosis factor-α (TNF-α) or transforming growth factor-β1 (TGF-β1). The effects of TNF-α (10 ng/ml) and/or TGF-β1 (2 ng/ml) were thus investigated in dust-exposed primary type II cell cultures. In control day 1 or day 3 cultures, TNF-α and/or TGF-β1 had little or no effect on the synthesis of type II cellular proteins, independent of whether the cells were exposed to dust. With PSOC 867 exposure, where ECM protein synthesis is elevated, TNF-α and TGF-β1 further increased both the absolute and relative rates of ECM synthesis on day 3 but had little effect on day 1. Each mediator increased expression of fibronectin mRNA, as well as of ECM fibronectin content, in a manner qualitatively similar to their effects on synthesis. Thus TNF-α and TGF-β1 modulate both ECM synthesis and fibronectin content in coal dust-exposed type II cell cultures.

TGF-β1 and fibroblast growth factor-1 modify fibroblast growth factor-2 production in type II cells

2000 ◽  
Vol 279 (6) ◽  
pp. L1038-L1046 ◽  
Author(s):  
Cheng-Ming Li ◽  
Jody Khosla ◽  
Ines Pagan ◽  
Paul Hoyle ◽  
Philip L. Sannes
Keyword(s):  
Growth Factor ◽  
Dna Synthesis ◽  
Fibroblast Growth Factor ◽  
Transforming Growth Factor ◽  
Alveolar Epithelium ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Fibroblast Growth ◽  
Tgf Β1

Fibroblast growth factor (FGF)-2, which stimulates DNA synthesis by type II cells in the lung, has been shown to be regulated by transforming growth factor (TGF)-β1, an important inflammatory cytokine, in vascular epithelium. The goal of this study was to determine if FGF-2 production by alveolar type II cells is modulated by TGF-β1 or FGF-1, which also stimulates DNA synthesis by type II cells. Isolated rat type II cells were exposed to 0–40 ng/ml of TGF-β1 or 0–500 ng/ml of FGF-1 in serum-free medium for 1–5 days. With a specific immunoassay, significant increases of FGF-2 protein in type II cell lysates to levels above those in control cells were achieved after 1 day of exposure to 100 ng/ml of FGF-1 and after 3 days of treatment with 8 ng/ml of TGF-β1. Similarly, transcripts for FGF-2 were dramatically increased above those in control cells with TGF-β1 or FGF-1, as were those for FGF receptor-1. These results demonstrate important regulatory links between FGF-2 and both TGF-β1 and FGF-1 in the alveolar epithelium that could contribute to the regulation of normal cell turnover, development, and the repair processes after injury in the lung.

MUC1 intracellular bioactivation mediates lung fibrosis

Thorax ◽  
2019 ◽  
Vol 75 (2) ◽  
pp. 132-142 ◽  
Author(s):  
Javier Milara ◽  
Beatriz Ballester ◽  
Paula Montero ◽  
Juan Escriva ◽  
Enrique Artigues ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Nuclear Translocation ◽  
Lung Fibroblasts ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Type Ii Cells ◽  
Nuclear Complex ◽  
Potential Biomarker ◽  
Tgf Β1

BackgroundSerum KL6/mucin 1 (MUC1) has been identified as a potential biomarker in idiopathic pulmonary fibrosis (IPF), but the role of MUC1 intracellular bioactivation in IPF is unknown.ObjectiveTo characterise MUC1 intracellular bioactivation in IPF.Methods and resultsThe expression and phosphorylation of Thr41 and Tyr46 on the intracellular MUC1-cytoplasmic tail (CT) was increased in patients with IPF (n=22) compared with healthy subjects (n=21) and localised to fibroblasts and hyperplastic alveolar type II cells. Transforming growth factor (TGF)-β1 phosphorylated SMAD3 and thereby increased the phosphorylation of MUC1-CT Thr41 and Tyr46 in lung fibroblasts and alveolar type II cells, activating β-catenin to form a phospho-Smad3/MUC1-CT and MUC1-CT/β-catenin nuclear complex. This nuclear complex promoted alveolar epithelial type II and fibroblast to myofibroblast transitions, as well as cell senescence and fibroblast proliferation. The inhibition of MUC1-CT nuclear translocation using the inhibitor, GO-201 or silencing MUC1 by siRNA, reduced myofibroblast transition, senescence and proliferation in vitro. Bleomycin-induced lung fibrosis was reduced in mice treated with GO-201 and in MUC1-knockout mice. The profibrotic lectin, galectin-3, directly activated MUC1-CT and served as a bridge between the TGF-β receptor and the MUC1-C domain, indicating TGF-β1-dependent and TGF-β1-independent intracellular bioactivation of MUC1.ConclusionsMUC1 intracellular bioactivation is enhanced in IPF and promotes fibrotic processes that could represent potential druggable targets for IPF.

scholarly journals Down-regulation of Human Type II Collagen Gene Expression by Transforming Growth Factor-β1 (TGF-β1) in Articular Chondrocytes Involves SP3/SP1 Ratio

2002 ◽  
Vol 277 (46) ◽  
pp. 43903-43917 ◽  
Author(s):  
Christos Chadjichristos ◽  
Chafik Ghayor ◽  
Jean-François Herrouin ◽  
Leena Ala-Kokko ◽  
Gunthram Suske ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Articular Chondrocytes ◽  
Type Ii Collagen ◽  
Transforming Growth Factor Β1 ◽  
Collagen Gene ◽  
Type Ii ◽  
Human Type ◽  
Tgf Β1

scholarly journals The miR-130a-3p/TGF-βRII Axis Participates in Inhibiting the Differentiation of Fibroblasts Induced by TGF-β1

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanhong Liu ◽  
Yan Ding ◽  
Yapeng Hou ◽  
Tong Yu ◽  
Hongguang Nie ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Immunofluorescence Assay ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Mouse Lung ◽  
Smad Signaling ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Pulmonary fibrosis (PF) is a chronic progressive interstitial lung disease that has a poor prognosis. Abnormal activation of transforming growth factor-β1 (TGF-β1) plays a crucial role in fibroblast differentiation. Mesenchymal stem cells (MSCs) are currently being considered for the treatment of PF, but the regulatory mechanisms are poorly understood. We co-cultured bone marrow-derived MSCs and mouse lung fibroblasts (MLg) in the presence of TGF-β1, and studied the protein/mRNA expression of fibrosis markers and related signaling pathways. The effects of miR-130a-3p and TGF-β receptor II (TGF-βRII) on the differentiation of MLg induced by TGF-β1 were studied using immunofluorescence assay, Western blot, and quantitative real-time PCR techniques, respectively. Our results showed that MSCs reversed the overexpression of fibrosis markers and TGF-β1/Smad signaling pathway proteins and mRNAs after TGF-β1 treatment and increased the level of miR-130a-3p. TGF-βRII was identified as a target of miR-130a-3p and was evaluated by dual-luciferase reporter assay. The miR-130a-3p/TGF-βRII axis could suppress the differentiation of lung fibroblasts via the TGF-β1/Smad signaling pathway, thereby reducing the process of PF.

scholarly journals Acetaldehyde stimulates the activation of latent transforming growth factor-β1 and induces expression of the type II receptor of the cytokine in rat cultured hepatic stellate cells

2002 ◽  
Vol 368 (3) ◽  
pp. 683-693 ◽  
Author(s):  
Anping CHEN
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Hepatic Stellate Cells ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Transforming Growth Factor Β1 ◽  
Collagen Gene ◽  
Type Ii ◽  
Underlying Mechanisms ◽  
Tgf Β1

Acetaldehyde, the major active metabolite of alcohol, induces the activation of hepatic stellate cells (HSC), leading to over-production of α1(I) collagen and ultimately causing hepatic fibrosis. The underlying mechanisms of this process remain largely unknown. Transforming growth factor-β1 (TGF-β1) is a potent inducer of α1(I) collagen production. Accumulating evidence has shown a potential role for TGF-β1 in alcohol-induced hepatic fibrogenesis. The aims of this study were to determine the effect of acetaldehyde on TGF-β signalling, to elucidate the underlying mechanisms as well as to evaluate its role in expression of α1(I) collagen gene in cultured HSC. It was hypothesized that acetaldehyde activated TGF-β signalling by inducing the expression of elements in the TGF-β signal transduction pathway, which might contribute to α1(I) collagen gene expression in cultured HSC. Initial results revealed that acetaldehyde activated TGF-β signalling in cultured HSC. Additional studies demonstrated that acetaldehyde stimulated the secretion and activation of latent TGF-β1, and induced the expression of the type II TGF-β receptor (Tβ-RII). Further experiments found cis- and trans-activating elements responsible for Tβ-RII gene expression induced by acetaldehyde. Activation of TGF-β signalling by acetaldehyde contributed to α1(I) collagen gene expression in cultured HSC. In summary, this report demonstrated that acetaldehyde stimulated TGF-β signalling by increasing the secretion and activation of latent TGF-β1 as well as by inducing the expression of Tβ-RII in cultured HSC. Results from this report provided a novel insight into mechanisms by which acetaldehyde stimulated the expression of α1(I) collagen in HSC and a better understanding of effects of alcohol (or acetaldehyde) on hepatic fibrogenesis.

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