Th9/IL-9 axis mediates airway fibrosis in traumatic tracheal stenosis via TGF-β1/SMAD2/3 signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus Norvegicus
SUBMITTER: 
Guangnan Liu
PROVIDER: PXD066983 | iProX | Wed Aug 06 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Venkatraman2012 - Interplay between PLS and TSP1 in TGF-β1 activation
The interplay between PLS (Plasmin) and TSP1 (Thrombospondin-1) in TGF-β1 (Transforming growth factor-β1)is shown using mathematical modelling and in vitro
experimentents.
This model is described in the article:
Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1.
Venkatraman L, Chia SM, Narmada BC, White JK, Bhowmick SS, Forbes Dewey C Jr, So PT, Tucker-Kellogg L, Yu H.
Biophys J. 2012 Sep 5;103(5):1060-8.
Abstract:
Transforming growth factor-β1 (TGF-β1) is a potent regulator of extracellular matrix production, wound healing, differentiation, and immune response, and is implicated in the progression of fibrotic diseases and cancer. Extracellular activation of TGF-β1 from its latent form provides spatiotemporal control over TGF-β1 signaling, but the current understanding of TGF-β1 activation does not emphasize cross talk between activators. Plasmin (PLS) and thrombospondin-1 (TSP1) have been studied individually as activators of TGF-β1, and in this work we used a systems-level approach with mathematical modeling and in vitro experiments to study the interplay between PLS and TSP1 in TGF-β1 activation. Simulations and steady-state analysis predicted a switch-like bistable transition between two levels of active TGF-β1, with an inverse correlation between PLS and TSP1. In particular, the model predicted that increasing PLS breaks a TSP1-TGF-β1 positive feedback loop and causes an unexpected net decrease in TGF-β1 activation. To test these predictions in vitro, we treated rat hepatocytes and hepatic stellate cells with PLS, which caused proteolytic cleavage of TSP1 and decreased activation of TGF-β1. The TGF-β1 activation levels showed a cooperative dose response, and a test of hysteresis in the cocultured cells validated that TGF-β1 activation is bistable. We conclude that switch-like behavior arises from natural competition between two distinct modes of TGF-β1 activation: a TSP1-mediated mode of high activation and a PLS-mediated mode of low activation. This switch suggests an explanation for the unexpected effects of the plasminogen activation system on TGF-β1 in fibrotic diseases in vivo, as well as novel prognostic and therapeutic approaches for diseases with TGF-β dysregulation.
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2024-09-02 | BIOMD0000000447 | BioModels
Project description:Objectives. Interleukin-17A (IL-17A) levels are increased in SSc skin and other organs but its role in fibrosis development is highly debated. Since epithelial cells are preferential targets of IL-17A, we aimed at investigating the role of IL-17A in the interactions between epidermis and dermis. Methods. Organotypic cultures of HD full human skin were challenged with IL-17A,TNF and TGF-β. Inflammatory mediators and type I collagen (col-I) levels were quantified. IL-17A- and TGF-β-induced changes in gene expression in full human skin were analysed by RNA sequencing. Results. In full human skin, TGF-β induced pro-fibrotic gene signature dominated by Wnt signalling. While IL-17A strongly promoted expression of many pro-inflammatory genes, it did not affect collagen gene levels but decreased Wnt signalling. At the protein level, IL-17A showed direct anti-fibrotic effects, as well as decreased by 2-fold TGF-β-triggered col-I production. Conclusions. We report here firstly, a novel model of fibrotic skin and secondly, that IL-17A acts as a potent anti-fibrotic factor in the full human skin. Furthermore, we show that IL-17A not only decreased ECM deposition by itself, but also counteracted TGF-β pro-fibrotic activities. Thus, IL-17A seems to play a dual role in SSc skin – strongly pro-inflammatory but anti-fibrotic, being an example that fibrosis and inflammation, although closely related, are two different processes. These data may help in directing and interpreting therapeutic approaches in SSc, since both, IL-17A and TGF-β, are target candidates in clinical trials.
2020-02-11 | GSE122305 | GEO
Project description:Connective tissue growthfactor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor-beta (TGF-beta) and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We have previously shown that keratinocytes in vitro downregulate TGF-beta induced expression of CTGF in fibroblasts by an interleukin-1 alfa (IL-1alfa) dependent mechanism. With this study we want to get a better overall perspective who fibroblasts respond on TGF-beta and in a TGF-Beta stinulated system, what effect addition of IL-1 alfa have. This to understand the expression of CTGF in human fibroblasts which in turn have implications for the pathogenesis of fibrotic conditions involving the skin. Microarray was performed on human skin fibroblast RNA from one patient, Fibroblasts were seeded in vitro as a control (Control, C), TGF-beta were added to fibroblasts and incubated for 16 h (addition of TGF-beta, T) and both IL-1alfa and TGF-beta were added to fibroblasts for 16 h (addition of IL-1alfa and TGF-beta, IT). Each condition (C,T and IT) were done in three replicates.
2016-04-14 | E-GEOD-69447 | biostudies-arrayexpress
Project description:Interventions: A:CEA-CART
Primary outcome(s): cytokines IL-1beta;cytokine IL-2R;cytokine IL-6;cytokine IL-8;cytokine IL-10;cytokine TNF-alpha;copy numbers of CART in vivo;serum CEA;tumor size
Study Design: Non randomized control
| 2668568 | ecrin-mdr-crc
Project description:Activated pancreatic stellate cells produce the fibrotic matrix in chronic pancreatitis and pancreatic cancer. In vitro protocols examining PSC biology have usually involved PSCs cultured on plastic, a non-physiological surface. However, PSCs cultured on physiological matrices e.g. MatrigelTM (normal basement membrane) and collagen (fibrotic pancreas), may have distinctly different behaviours compared to cells cultured on plastic. Therefore, we aimed to compare PSC gene expression after culture on plastic, MatrigelTM and collagen I. Total RNA from stellate cells in 10 cm Petri dishes was isolated by Qiagen RNeasy Mini Plus kit as per manufacturer’s instructions. The Agilent 2100 Bioanalyzer (Agilent Technologies Inc. Santa Clara, CA) was used for quality control of the isolated total RNA. Gene expression profiles of rat PSCs cultured on MatrigelTM, collagen I and plastic were analysed by whole rat genome microarray purchased from Affymetrix (Rat Gene 1.0 ST Array). This array was able to detect 27,342 rat genes, with approximately 26 probes on average per gene (referred to as a probe set).
2013-01-17 | E-GEOD-43496 | biostudies-arrayexpress
Project description:Previous studies have reported that low-intensity pulsed ultrasound (LIPUS) can alleviate cartilage degradation in osteoarthritis (OA). However, the functions and mechanisms of LIPUS in synovial fibrosis with OA require further study. To investigate the role of the PI3K/AKT signaling pathway in synovial fibrosis and in LIPUS treatment in synovial fibrosis, a TGF-stimulated rat FLS cell model and a rat OA animal model based on anterior cruciate ligament transection (ACLT) and partial medial meniscectomy (MMx) were used. The results revealed that LIPUS delayed the progression of OA. Masson staining revealed that LIPUS reduced the collagen deposition of synovial tissue in OA rats. Correspondingly, immunofluorescence demonstrated that LIPUS significantly downregulated the expression of α-SMA and Col3a1 in OA rats. Moreover, TGF-β stimulation upregulated fibrosis markers at the mRNA and protein levels in FLS, as well as increased phosphorylation-dependent activation of the PI3K/Akt pathway. 740Y-P was found to promote the fibrotic change of FLS induced by TGF-β, but LY294002 reduced its expression. However, LIPUS inhibits the fibrotic change and activation of the PI3K/Akt pathway in FLS under stimulation of TGF-β. In conclusion, LIPUS alleviates synovial fibrosis by blocking the PI3K/AKT pathway.
2025-03-23 | PXD061090 | Pride
Project description:<p>The purpose of this study is to discover in vivo cytokine expression quantitative trait locus (eQTL) interactions from a cohort of patients with systemic lupus erythematosus. 157 lupus patients were enrolled in a clinical trial to test the efficacy and safety of an anti-IL-6 monoclonal antibody. At three time points, we measured interferon (IFN) status, anti-IL-6 drug exposure and genome-wide gen expression. We identified 4,818 cis-eQTLs and then observed a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 exposure.</p>
| phs001702 | dbGaP
Project description:Connective tissue growthfactor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor-beta (TGF-beta) and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We have previously shown that keratinocytes in vitro downregulate TGF-beta induced expression of CTGF in fibroblasts by an interleukin-1 alfa (IL-1alfa) dependent mechanism. With this study we want to get a better overall perspective who fibroblasts respond on TGF-beta and in a TGF-Beta stinulated system, what effect addition of IL-1 alfa have. This to understand the expression of CTGF in human fibroblasts which in turn have implications for the pathogenesis of fibrotic conditions involving the skin.
2016-04-14 | GSE69447 | GEO
Project description:Renal scarring is a serious complication of chronic pyelonephritis due to vesicoureteral reflux, and requires specific biomarker for indication of early intervention. We investigated global expression profile of kidney during renal scarring formation using rat pyelonephritis model. An inoculum of the DS-17 strain Escherchia coli was injected directly into renal cortex of Wister rat. Histologically, renal scarring developed during 3 and 4 weeks after injection. The time course expression profile of approximately 20,500 genes was analyzed using high density oligonucleotide microarray followed by validation using real time RT-PCR. Most of up-regulated genes during this experimental renal scarring were associated with immune and defense response, including cytokines, chemokines, their receptors, complements, and adhesion molecules as well as proteins related to extra cellular matrix. These genes were up-regulated as early as 1 week after injection when histological examination did not show fibrotic change yet, peaked at 2 weeks and gradually decreased thereafter. However, a subset of cytokine genes is persistently activated even in 6 weeks after the injection, which are involved in TGF-β related tissue regeneration pathway or IL-1β related pathway. The products of these genes may potentially be the source of novel non-invasive diagnostic or prognostic biomarkers for renal scarring. Keywords: renal scarring, TGF-β , IL-1β
2007-02-22 | GSE7087 | GEO
Project description:Atrial fibrillation (AF) and heart failure (HF) are mutually reinforcing, and the prognosis for both diseases is poor. Vericiguat is the first oral soluble guanylate cyclase (sGC) stimulator to be approved for the treatment of symptomatic, ejection fraction-reduced chronic heart failure (HFrEF) in adults. It exerts a general therapeutic effect on cardiovascular diseases, with a particular efficacy in the treatment of HF. However, the mechanism of vericiguat treatment of atrial fibrillation remains unclear. The objective of this study was to investigate the potential mechanism of vericiguat in the treatment of atrial fibrillation. A retrospective analysis was conducted to investigate the effects of vericiguat on patients with heart failure and paroxysmal AF. Furthermore, the effects of vericiguat on AF and the degree of myocardial fibrosis in rat AF models and cells were observed. It was found that vericiguat can control the recurrence of AF in clinical studies and can control the fibrosis of AF rats in vivo and in vitro experiments. RNA-Seq sequencing revealed that the TGF-β1/Smad pathway in cells treated with vericiguat was significantly enriched. In vitro validation demonstrated that the anti-fibrotic effect of Vericiguat was weakened by the TGF-β1/Smad pathway when Protein Kinase G (PKG) was knocked down. The findings indicate that vericiguat can inhibit myocardial fibroblast activation and collagen synthesis via the TGF-β1/Smad pathway, thereby exerting a controlling effect on the recurrence of atrial fibrillation.
2025-07-23 | GSE278356 | GEO