A novel non-canonical signaling pathway mediates TGF-β1-induced glucocorticoid insensitivity in epithelial cells
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ABSTRACT:
PROVIDER: PRJNA414116 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6165800_1.fastq.gz | Fastqsanger.gz | |||
| SRR6165800_2.fastq.gz | Fastqsanger.gz | |||
| SRR6165810_1.fastq.gz | Fastqsanger.gz | |||
| SRR6165810_2.fastq.gz | Fastqsanger.gz | |||
| SRR6165801_1.fastq.gz | Fastqsanger.gz |
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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.
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2015-06-30 | E-GEOD-63659 | biostudies-arrayexpress
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.
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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.
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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
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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.
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2022-04-28 | GSE201506 | GEO
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