Expression changes in respiratory epithelial cells when treated with TGF-β1
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE267358 | GEO | 2024/05/31
REPOSITORIES: GEO
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Project description:TGF-β1 is involved in various biological processes through downstream signals including SMAD, Akt, Erk, etc. TGF-β1 overexpressed by harmful stimuli can act as a causative factor in diseases such as accumulation of extracellular matrix and development of cancerous characteristics. Therefore, we sought to compare changes in expression of intracellular miRNAs to study diseases caused by TGF-β1. In our study, we aimed to discover therapeutic targets for TGF-β1-induced disease by investigating changes in miRNA expression and identifying the correlation between genes that can be regulated by miRNA.
2024-07-24 | GSE267490 | GEO
Project description:Myocardial infarctions cause hypoxic injury to downstream tissue and a consequent fibrotic remodeling process to replace injured tissue with a scar. Scar formation occurs through phases of wound healing in which stimuli such as transforming growth factor-beta (TGF-β) drive cardiac fibroblasts to activate into a myofibroblast phenotype and deposit matrix molecules that form a scar. While this is necessary to repair injured tissue, excessive fibrosis commonly occurs which is correlated with heart failure. Therefore, defining cardiac fibroblast phenotypes under hypoxic stimuli and TGF-β is essential for understanding and treating pathological fibrosis. We robustly characterized fibroblast phenotype through immunofluorescence, quantitative RT-PCR, and proteomic analysis, after either TGF-β treatment or hypoxia durations that mimic acute hypoxic injury post-infarction. We find that hypoxic fibroblasts respond to low oxygen with increased hypoxia inducible factor 1 (HIF-1) but not HIF-2 activity by 4h. This is accompanied by increased gene and protein levels of VEGFA and LOX, respectively, which are both targets of HIF-1. Both TGF-β1 and hypoxia inhibit proliferation by 24h. While TGF-β1 treatment upregulated various fibrotic pathways, hypoxia causes a global reduction in protein synthesis, including collagen biosynthesis. This study discerns overlapping from distinctive outcomes of TGF-β1 and hypoxia treatment, which is important for elucidating their roles in fibrotic remodeling post-MI.
2024-07-03 | PXD051197 | Pride
Project description:These data show that the genes that distinguish myofibroblasts from fibroblasts are myriad, and that some genes not traditionally associated with myofibroblast differentiation may serve as novel therapeutic targets for fibrosing disorders. Gene expression levels were assessed from total RNA on the Affymetrix U219 microarray. Here, we use transforming growth factor-β1 (TGF-β1) and prostaglandin E2 (PGE2), which has recently been shown to reverse myofibroblast differentiation, to investigate the transcriptomic changes that occur during TGF-β1-induced differentiation and PGE2-induced de-differentiation of myofibroblasts.
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Project description:Fibrotic diseases have significant health impact and have been associated with differentiation of the resident fibroblasts into myofibroblasts. In particular, stiffened extracellular matrix and TGF-β1 in fibrotic lesions have been shown to promote pathogenic myofibroblast activation and progression of fibrosis in various tissues. To better understand the roles of mechanical and chemical cues on myofibroblast differentiation and how they may crosstalk, we cultured primary valvular interstitial cells (VICs) isolated from porcine aortic valves and studied how traditional TCPS culture, which presents a non-physiologically stiff environment, and TGF-β1 affect native VIC phenotypes. We carried out gene expression profiling using porcine genome microarrays from Affymetrix and found that traditional TCPS culture induces major changes in gene expression of native VICs, rendering these cells more activated and similar to cells treated with TGF-β1. We also monitored time-dependent effects induced by TGF-β1 by examining gene expression changes induced by TGF-β1 at 8 hours and 24 hours. Porcine aortic VICs were isolated and cultured with or without TGF-β1 treatment for RNA extraction and hybridization on Affymetrix microarrays. We included 3 biological replicates for each condition. P0 VICs were freshly isolated cells which had not been cultured. P2 VICs were cells that had been passaged 2 times and cultured on plastic plates in low serum media. Some of the P2 VICs were treated with TGF-β1 at 5ng/ml for 8 hours or 24 hours. All the control and TGF-β1-treated conditions were collected at the same time on day 3 of culture.
2013-09-02 | E-GEOD-48839 | biostudies-arrayexpress
Project description:Hepatic stellate cell (HSC) activation induced by transforming growth factor β (TGF-β1) plays a pivotal role in the fibrogenesis. The complex downstream mediators of TGF-β1 are largely unknown. Here, proteomics analysis and biological validation demonstrated that methionine adenosyltransferase 2A (MAT2A) was significantly upregulated in a CCl4-induced fibrosis mice model and a small molecule NPLC0393, known to block TGF-β1/Smad3 signaling, inhibited its upregulation. In HSC cells, TGF-β1 induced elevation of MAT2A and MAT2β expression as well as reduction of S-adenosylmethionine (SAM) content, which further promoted HSC activation. Functionally, in vivo and in vitro knockdown of MAT2A alleviated CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitated hepatic fibrosis and abolished therapeutic effect of NPLC0393. TGF-β1 induced p65 phosphorylation and NF-κB activation, thereby promoted the transcription of MAT2A and its protein expression. In addition, overexpression of p65 abrogated NPLC0393 mediated inhibition of HSC activation. This study identified a novel pathway TGF-β1/p65/MAT2A that was involved in the regulation of intracellular SAM contents and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis.
2019-11-12 | PXD011135 | Pride
Project description:Hepatic stellate cell (HSC) activation induced by transforming growth factor β (TGF-β1) plays a pivotal role in the fibrogenesis. The complex downstream mediators of TGF-β1 are largely unknown. Here, proteomics analysis and biological validation demonstrated that methionine adenosyltransferase 2A (MAT2A) was significantly upregulated in a CCl4-induced fibrosis mice model and a small molecule NPLC0393, known to block TGF-β1/Smad3 signaling, inhibited its upregulation. In HSC cells, TGF-β1 induced elevation of MAT2A and MAT2β expression as well as reduction of S-adenosylmethionine (SAM) content, which further promoted HSC activation. Functionally, in vivo and in vitro knockdown of MAT2A alleviated CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitated hepatic fibrosis and abolished therapeutic effect of NPLC0393. TGF-β1 induced p65 phosphorylation and NF-κB activation, thereby promoted the transcription of MAT2A and its protein expression. In addition, overexpression of p65 abrogated NPLC0393 mediated inhibition of HSC activation. This study identified a novel pathway TGF-β1/p65/MAT2A that was involved in the regulation of intracellular SAM contents and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis.
2019-11-12 | PXD011134 | Pride
Project description:Limited therapeutic responses to glucocorticoids in chronic inflammatory disease are partly attributable to interleukins and transforming growth factor-β1 (TGF-β1). Global inhibition of TGF-β1 carries known risks, including autoimmune disease. Here we elucidate the signaling pathway subserving modulation of glucocorticoid activity by TGF-β1. The proteomic response of airway epithelial cells to TGF-β1 revealed 24 candidate proteins of which 3 were prioritized by exclusion of changes induced by: TGF-β2, which lacks the modulatory activity of TGF-β1 and TGF-β3; and those of TGF-β1 that were prevented by small molecule inhibitors of non-canonical TGF-β1 signaling, that did not prevent glucocorticoid modulation. Pharmacological and genetic approaches establish that TGF-β1-induced glucocorticoid insensitivity is mediated by a novel signaling cascade involving LIM domain kinase 2 mediated phosphorylation of phospho-cofilin1 that activates phospholipase D to generate the effector(s) (lyso)phophatidic acid. This study identifies several promising drug targets that potentially enable safe modulation of TGF-β1 in chronic inflammatory diseases.
2019-01-27 | GSE104908 | GEO
Project description:Tumor-associated neutrophils are found in many types of cancer and are often reported to contribute to negative outcomes. Several studies have shown that the presence of TGF-β in the tumor microenvironment contributes to the skewing of neutrophils to have a more pro-tumor phenotype. However, the direct effects of TGF-β on neutrophil signaling and migration are unclear. We sought to characterize TGF-β signaling in both primary human neutrophils and the neutrophil-like cell line HL-60 and determine whether TGF-β directly induces neutrophil migration. We found that TGF-β1 does not induce neutrophil migration in either a transwell or an underagarose migration assay. However, TGF-β1 does activate signals canonically through SMAD3 and noncanonically through ERK1/2 in neutrophils in a time and dose-dependent manner. Additionally, TGF-β1 present in the tumor-conditioned media (TCM) is responsible for SMAD3 activation. Moreover, we discovered that TCM from aggressive breast cancer cells induces neutrophils to secrete leukotriene B4 (LTB4), which is a lipid mediator important for amplifying neutrophil recruitment. However, we found that TGF-β1 alone does not induce secretion of LTB4. We next performed RNA-sequencing to evaluate the effects of TGF-β1 and TCM on the neutrophil transcriptome. We found that TGF-β1 and TCM result in changes in gene transcription in HL-60 cells, specifically of two pro-tumor genes OSM and VEGFA. Together, our findings characterize the effects of TGF-β1 on neutrophil signaling, migration, and gene expression that can be applied to understanding the changes in neutrophils that occur in the tumor microenvironment.
2023-08-10 | GSE230490 | GEO
Project description:Background: Increased Galectin 3-binding protein (Lgals3bp) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering the crucial role of transforming growth factor-β1 (TGF-β1) in the emergence of these diseases, the present study tested the hypothesis that Lgals3bp regulates the TGF-β1 signaling pathway. Methods: The expression levels of Lgals3bp and TGF-β1 were analyzed in patients with non-alcoholic steatohepatitis (NASH) and HCC. Multiple omics techniques, such as RNA-sequencing, transposase-accessible chromatin-sequencing assay, and liquid chromatography-tandem mass spectrometry proteomics, were used to identify the regulatory mechanisms for the Lgals3bp-TGF-β1 axis. Moreover, the effects of altered TGF-β1 signaling in chronic inflammatory conditions were investigated in conditional Lgals3bp-knockin and Lgals3bp-knockout mice. Results: In patients with NASH and HCC, the levels of Lgals3bp and TGF-β1 exhibited positive correlations. Stimulation of Lgals3bp by the inflammatory cytokine interferon α in HCC cells or ectopic overexpression of Lgals3bp in hepatocytes promoted the expression levels of TGFB1. Aggravated fibrosis was observed in the livers of hepatocyte-specific Lgals3bp knock-in mice, with increased TGF-β1 levels. Lgals3bp directly bound to and assembled integrin αV, an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton. The released TGF-β1 activated JunB transcription factor, which in turn promoted the TGF-β1 positive feedback loop. Lgals3bp deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis. Finally, Lgals3bp depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1. Conclusion: Lgals3bp plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway, making it a promising therapeutic target in TGF-β1-related diseases.
2024-07-06 | GSE271354 | GEO
Project description:Background: Increased Galectin 3-binding protein (Lgals3bp) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering the crucial role of transforming growth factor-β1 (TGF-β1) in the emergence of these diseases, the present study tested the hypothesis that Lgals3bp regulates the TGF-β1 signaling pathway. Methods: The expression levels of Lgals3bp and TGF-β1 were analyzed in patients with non-alcoholic steatohepatitis (NASH) and HCC. Multiple omics techniques, such as RNA-sequencing, transposase-accessible chromatin-sequencing assay, and liquid chromatography-tandem mass spectrometry proteomics, were used to identify the regulatory mechanisms for the Lgals3bp-TGF-β1 axis. Moreover, the effects of altered TGF-β1 signaling in chronic inflammatory conditions were investigated in conditional Lgals3bp-knockin and Lgals3bp-knockout mice. Results: In patients with NASH and HCC, the levels of Lgals3bp and TGF-β1 exhibited positive correlations. Stimulation of Lgals3bp by the inflammatory cytokine interferon α in HCC cells or ectopic overexpression of Lgals3bp in hepatocytes promoted the expression levels of TGFB1. Aggravated fibrosis was observed in the livers of hepatocyte-specific Lgals3bp knock-in mice, with increased TGF-β1 levels. Lgals3bp directly bound to and assembled integrin αV, an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton. The released TGF-β1 activated JunB transcription factor, which in turn promoted the TGF-β1 positive feedback loop. Lgals3bp deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis. Finally, Lgals3bp depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1. Conclusion: Lgals3bp plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway, making it a promising therapeutic target in TGF-β1-related diseases.
2024-07-06 | GSE271352 | GEO