YAP mediates TNF effect on pro-fibrotic genes expression
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ABSTRACT:
PROVIDER: PRJNA799310 | ENA |
REPOSITORIES: ENA
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Project description:YAP/TAZ are transcription co-factors recently described responsive to pro-inflammatory cytokines and involved in inflammatory-related disorders. However, the role of tumor necrosis factor (TNF), a major pro-inflammatory cytokine, on YAP signaling is not well understood and controversial. Here, we observe in vitro, using wild type and YAP knockout HEK293 cells, that TNF triggers YAP nuclear translocation and transcriptional activity, thus being dependent on Rho family of GTPases. In response to TNF, YAP transcriptional activity orientates cell fate toward survival. Transcriptional analysis with Nanostring technology reveals that YAP modulates TNF-induced increase in fibro-inflammatory pathways such as NF-κB, inflammasomes, cytokines or chemokines signaling as well as pro-fibrotic pathways involving TGF-β and extracellular matrix remodeling. Therefore, in response to TNF, YAP acts as a sustainer of the inflammatory response and as a molecular link between inflammation and fibrotic processes. This work identifies that YAP is critical to drive several biological effects of TNF which are involved in cancer and inflammatory disorders.
2022-03-09 | GSE194136 | GEO
Project description:Objective: To evaluate gene expression profiles in patients with advanced cirrhosis compared with healthy controls (HC). Results: Patients with advanced cirrhosis exhibit an unbalanced systemic response involving pro-fibrotic / protective signatures that could be contributing to the pathogenesis of cirrhosis and also to that of the extra-hepatic complications of this disease.
2016-02-14 | E-MTAB-3338 | biostudies-arrayexpress
Project description:Epoxygenases belong to the cytochrome P450 family and they generate epoxyeicosatrienoic acids (EETs) known to have anti-inflammatory effects but little is known about their role in macrophage function. By high-throughput sequencing of RNA (RNA-seq) in primary macrophages derived fromrodents and humans, we establish the relative expression of epoxygenases in these cells. Zinc-finger nuclease-mediated targeted gene deletion of the major rat macrophage epoxygenase Cyp2j4 (orthologue of human CYP2J2),resulted inreduced EET synthesis. Cyp2j4-/-macrophages have relatively increased PPARγ levels and show a pro-fibrotic transcriptome,displayingover-expression of a specific subset of genes (260 transcripts) primarily involved in extracellular matrix, with fibronectin being the most abundantly expressed transcript.Fibronectin expression is under the control of epoxygenase activity in human and rat primary macrophages. In keeping with the invitro findings, Cyp2j4-/- rats show up-regulation of type I collagen following unilateral ureter obstruction (UUO) of the kidney and quantitative proteomics analysis (LC-MS/MS) showed increased renal type I collagen and fibronectin protein abundance resulting from experimentally induced crescentic glomerulonephritis in these rats. Taken together, these results identify the rat epoxygenase Cyp2j4 as a determinant of a pro-fibrotic macrophage transcriptome that could have implications in various inflammatory conditions depending on macrophage function. Gene expression profile generated for macrophages in wild type and Cyp2j4 KO WKY rats
2015-02-10 | E-GEOD-65715 | biostudies-arrayexpress
Project description:YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells (AECs). We investigated whether persistent YAP/TAZ AEC signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+/TAZ+ AECs and increased transcriptional target expression. Pharmacological YAP/TAZ activation in human AEC organoids and in murine AT2 cell organoids generated with genetic Yap/Taz activation (YTactive) (via deletion of Hippo-kinases Stk3/4), resulted in phenotype shifts into aberrant transitional and airway-like states. Bleomycin injury of YTactive mice resulted in persistent fibrotic remodeling at 28- and 56-days post-bleomycin injury. Gene promoter activity associated with transitional cell markers (Krt19, Hopx, and Runx2) was increased in YTactive AT2 cells. Immunofluorescent staining showed a loss of AT2 associated Cebpa and increased Krt19 in YTactive lineage traced AT2 cells 28 days post-injury. Inhibition of Yap/Taz using Verteporfin resulted in improved lung repair in YTactive mouse lungs, including restored Cebpa and decreased Krt19+ transitional cells. These findings demonstrate sustained Yap/Taz activation drives abnormal alveolar repair and persistent fibrotic remodeling. Blocking aberrant persistent Yap/Taz activity promotes adaptive repair and has potential as a therapeutic strategy for pulmonary fibrosis.
2026-06-02 | GSE327565 | GEO
Project description:YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells (AECs). We investigated whether persistent YAP/TAZ AEC signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+/TAZ+ AECs and increased transcriptional target expression. Pharmacological YAP/TAZ activation in human AEC organoids and in murine AT2 cell organoids generated with genetic Yap/Taz activation (YTactive) (via deletion of Hippo-kinases Stk3/4), resulted in phenotype shifts into aberrant transitional and airway-like states. Bleomycin injury of YTactive mice resulted in persistent fibrotic remodeling at 28- and 56-days post-bleomycin injury. Gene promoter activity associated with transitional cell markers (Krt19, Hopx, and Runx2) was increased in YTactive AT2 cells. Immunofluorescent staining showed a loss of AT2 associated Cebpa and increased Krt19 in YTactive lineage traced AT2 cells 28 days post-injury. Inhibition of Yap/Taz using Verteporfin resulted in improved lung repair in YTactive mouse lungs, including restored Cebpa and decreased Krt19+ transitional cells. These findings demonstrate sustained Yap/Taz activation drives abnormal alveolar repair and persistent fibrotic remodeling. Blocking aberrant persistent Yap/Taz activity promotes adaptive repair and has potential as a therapeutic strategy for pulmonary fibrosis.
2026-06-02 | GSE327686 | GEO
Project description:IL-5 increases pro-fibrotic and pro-inflammatory signalling in severe asthmatic fibroblasts
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Project description: Not available
| S-EPMC10734534 | biostudies-literature
Project description:Pulmonary fibrosis (PF) is a life-threatening condition characterised by excessive extracellular matrix deposition and tissue scarring. While much of PF research has focused on alveolar epithelial cells and fibroblasts, endothelial cells have emerged as active contributors to the disease initiation, especially in the context of systemic exposure to pro-fibrotic substances. Here, we investigate early transcriptomic and secretory responses of human umbilical vein endothelial cells (HUVEC) to subtoxic doses of bleomycin, a known pro-fibrotic agent, and TGF-beta, a key cytokine in fibrosis. Bleomycin exposure induced a rapid and extensive shift in the endothelial transcriptional programme, including signatures of endothelial to mesenchymal transition, cellular senescence, and immune cell recruitment. These findings suggest endothelial cells as early initiators of pro-fibrotic signals, independent of contributions from other cell types. In contrast, TGF-beta effects were limited and transient, indicating its pro-fibrotic action may require another initial stimulus and interplay with other cells like fibroblasts. This study highlights the sensitivity of endothelial cells to systemic pro-fibrotic exposure and provides a blueprint of early pro-fibrotic mechanisms, emphasising their pivotal role in PF pathogenesis.
2025-05-26 | GSE286040 | GEO
Project description:Fibrosis is a hallmark feature of airway remodeling in asthma. However, the exact molecular mechanisms driving its development and progression remain inadequately understood. Interleukin-5 (IL-5) plays a potent role in the inflammatory response associated with eosinophils and asthma pathophysiology, but its direct impact on lung fibroblasts and contribution to fibrosis have yet to be fully explored. In our study, we investigated the pro-fibrotic effects of IL-5 on human lung fibroblasts derived from asthmatic and normal subjects. Following IL-5 stimulation, these fibroblasts were subjected to a series of experiments to assess IL-5’s impact on fibrosis. Our findings reveal that IL-5 triggers the release of several extracellular matrix (ECM) components, and disrupts the balance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) . This imbalance further disrupts the MMP/TIMP ratio. Additionally, IL-5 stimulation promotes the release of pro-inflammatory and pro-fibrotic cytokines, Overall, these findings indicate a novel pro-fibrotic role of IL-5 through its direct action on lung fibroblasts, offering valuable insights into the therapeutic potential of targeting IL-5 to mitigate or possibly reverse airway remodeling in asthma.
2025-04-11 | GSE285468 | GEO
Project description:Pro-fibrotic and pro-inflammatory genes driven by steroid hormone imbalance in the prostate
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