Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA136191 | ENA |
REPOSITORIES: ENA
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Project description:Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the pro-inflammatory cytokines, TNF-α and IFN-γ reverses fibroblast resistance to apoptosis. The goal of this study was to investigate the underlying mechanism. Based on an initial interrogation of the transcriptomes of unstimulated and TNF-α and IFN-γ-stimulated primary lung fibroblasts and the lung fibroblast cell line, MRC5, we show here that among Fas-signaling pathway molecules, Fas expression was increased ~6-fold in an NF-κB and p38mapk-dependent fashion. Prevention of the increase in Fas expression using Fas siRNAs blocked the ability of TNF-α and IFN-γ to sensitize fibroblasts to Fas ligation induced-apoptosis; while enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. They also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant. To investigate the mechanism by which TNF-α and IFN-γ reprogram fibroblasts from resistance to sensitivity to Fas-ligation-induce apoptosis, we exposed human primary lung fibroblasts from an IPF patient (FS087) and non-disease control subject (N78) and the human fetal lung fibroblast cell lung (MRC-5) to TNF-α (10 ng/ml) and IFN-γ (50 U/ml) for 36 hr and analyzed changes in their transcriptomes using Affymetrix microarrays.
2011-01-13 | E-GEOD-26594 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the pro-inflammatory cytokines, TNF-α and IFN-γ reverses fibroblast resistance to apoptosis. The goal of this study was to investigate the underlying mechanism. Based on an initial interrogation of the transcriptomes of unstimulated and TNF-α and IFN-γ-stimulated primary lung fibroblasts and the lung fibroblast cell line, MRC5, we show here that among Fas-signaling pathway molecules, Fas expression was increased ~6-fold in an NF-κB and p38mapk-dependent fashion. Prevention of the increase in Fas expression using Fas siRNAs blocked the ability of TNF-α and IFN-γ to sensitize fibroblasts to Fas ligation induced-apoptosis; while enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. They also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant.
2011-01-13 | GSE26594 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts and continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contibributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, novel flow cytometry strategies to quantify lung fibroblast subsets and transcriptional profiling of lung fibroblasts by bulk and single cell RNA-sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued pro-fibrotic functions of lung fibroblasts. Our studies provide novel insights into the mechanisms that contribute to fibroblast survival, persistence and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis prevents fibrosis resolution.
2020-11-18 | GSE161648 | GEO
Project description:Defective Fas signaling causes autoimmune lymphoproliferative syndrome (ALPS). While defective apoptosis may impair negative selection and removal of autoreactive B lymphocytes, Fas transmits also non-apoptotic signals. We show herethat transient Fas ligation in CD40L-stimulated human B cells specifically decreased the mTOR axis activation without causing apoptosis. This signal modulation was absent in ALPS patients. Rather, mTOR signaling was enhanced in germinal center (GC) B cells and plasmablasts derived from a ALPS patient lymph node . Mechanistically, transient Fas engagement induced recruitment of DAXX to the activated Fas complex and nuclear exclusion of PTEN. Likewise, Fas stimulation promoted expression of transcripts like MYC and CXCR4, that regulate GC formation and fate decisions of established GC B cells. We suggest that non-apoptotic Fas signaling has a physiological impact on activated B cell fate decisions explaining the effectiveness of mTOR inhibitors in the treatment of ALPS autoimmunity.
2024-04-08 | PXD017601 | Pride
Project description:Webb2002 - Fas/FasL mediated tumor T-cell interaction
This deterministic model of
immunological surveillance involving tumour cell–T-lymphocyte
interaction, cell surface expression of Fas/FasL, and their
secreted soluble forms.
This model is described in the article:
Cells behaving badly: a
theoretical model for the Fas/FasL system in tumour
immunology.
Webb SD, Sherratt JA, Fish RG.
Math Biosci 2002 Sep-Oct; 179(2):
113-129
Abstract:
One proposed mechanism of tumour escape from immune
surveillance is tumour up-regulation of the cell surface ligand
FasL, which can lead to apoptosis of Fas receptor (Fas)
positive lymphocytes. Based upon this 'counterattack', we have
developed a mathematical model involving tumour cell-lymphocyte
interaction, cell surface expression of Fas/FasL, and their
secreted soluble forms. The model predicts that (a) the
production of soluble forms of Fas and FasL will lead to the
down-regulation of the immune response; (b) matrix
metalloproteinase (MMP) inactivation should lead to increased
membrane FasL and result in a higher rate of Fas-mediated
apoptosis for lymphocytes than for tumour cells. Recent studies
on cancer patients lend support for these predictions. The
clinical implications are two-fold. Firstly, the use of broad
spectrum MMP inhibitors as anti-angiogenic agents may be
compromised by their adverse effect on tumour FasL
up-regulation. Also, Fas/FasL interactions may have an impact
on the outcome of numerous ongoing immunotherapeutic trials
since the final common pathway of all these approaches is the
transduction of death signals within the tumour cell.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000661.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000661 | BioModels
Project description:Webb2002 - Fas/FasL mediated tumor T-cell interaction
This deterministic model of
immunological surveillance involving tumour cell–T-lymphocyte
interaction, cell surface expression of Fas/FasL, and their
secreted soluble forms.
This model is described in the article:
Cells behaving badly: a
theoretical model for the Fas/FasL system in tumour
immunology.
Webb SD, Sherratt JA, Fish RG.
Math Biosci 2002 Sep-Oct; 179(2):
113-129
Abstract:
One proposed mechanism of tumour escape from immune
surveillance is tumour up-regulation of the cell surface ligand
FasL, which can lead to apoptosis of Fas receptor (Fas)
positive lymphocytes. Based upon this 'counterattack', we have
developed a mathematical model involving tumour cell-lymphocyte
interaction, cell surface expression of Fas/FasL, and their
secreted soluble forms. The model predicts that (a) the
production of soluble forms of Fas and FasL will lead to the
down-regulation of the immune response; (b) matrix
metalloproteinase (MMP) inactivation should lead to increased
membrane FasL and result in a higher rate of Fas-mediated
apoptosis for lymphocytes than for tumour cells. Recent studies
on cancer patients lend support for these predictions. The
clinical implications are two-fold. Firstly, the use of broad
spectrum MMP inhibitors as anti-angiogenic agents may be
compromised by their adverse effect on tumour FasL
up-regulation. Also, Fas/FasL interactions may have an impact
on the outcome of numerous ongoing immunotherapeutic trials
since the final common pathway of all these approaches is the
transduction of death signals within the tumour cell.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000661.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000661 | BioModels
Project description:Non-alcoholic fatty liver disease (NAFLD) is a major public health burden and it covers a spectrum of diseases. NAFLD starts with the accumulation of lipid droplets (LDs) within hepatocytes (steatosis). Part of the challenge of studying the mechanistic processes involved in LD accumulation and their implications on the pathogenesis of human NAFLD is due to the available models. Investigating hepatic LDs in humans is challenging and relies on liver biopsies, meaning only cross-sectional data be obtained. On the other hand, LD patterns in in vitro models are poorly defined and rarely reported. Diacylgylcerol acyltransferase (DGAT)2 is one of two enzymes that carry out the final committed step in triacylglycerol (TAG) synthesis. It is unclear whether the enzymes are able to compensate for each other or whether they have distinct roles. It has been hypothesised that DGAT1 primarily utilises exogenous fatty acids and DGAT2 uses de novo-derived fatty acids. Given the important role of this enzyme in TAG synthesis and accumulation, the aims of this study are first to create a cellular model of intrahepatocellular TAG accumulation by manipulating nutritional substrates and to investigate intracellular metabolism in wildtype and DGAT2 knockout cells under these conditions. The experimental workflow for this study is as follows: Huh7 cells (either wild type or knockout) were grown in media containing 11 mM glucose and 2% human serum (HS) for seven days before additional sugars and fatty acids (FAs) were added for a further seven days. All treatments contained 11 mM glucose and 2% HS, either with 200 µM FAs (low fat low sugar; LFLS), 5.5 mM fructose + 200 µM FAs (low fat high sugar; LFHS) or 5.5 mM fructose + 800 µM FAs (high fat high sugar; HFHS). FA metabolism, lipid droplet characteristics and transcriptomic signatures were investigated.
2020-08-21 | E-MTAB-7884 | biostudies-arrayexpress
Project description:Comparison of SMC resistant and sensitive to TGF and Fas ligation by CH11 antibody Keywords: other
2005-04-13 | GSE2522 | GEO
Project description:Comparison of SMC resistant and sensitive to TGF and Fas ligation by CH11 antibody
2008-06-12 | E-GEOD-2522 | biostudies-arrayexpress
Project description:TNF-like ligand 1A (TL1A) is a member of TNF receptor superfamily and involved in the pathogenesis of autoimmune diseases by inducing apoptosis via intracellular death domain or promoting inflammation through the activation of NFκB by binding to its specific receptor death receptor 3 (DR3). Meanwhile, decoy receptor 3 (DcR3) competitively binds soluble TL1A in addition to Fas-ligand (FasL) and LIGHT and inhibits the signaling of TL1A via DR3. DcR3 overexpressed in rheumatoid synovial fibroblasts (RA-FLS) stimulated with inflammatory cytokines such as TNFα or IL-1β inhibits Fas-induced apoptosis. In contrast, DcR3 inhibited cell proliferation induced by inflammatory cytokines via membrane-bound TL1A expressed on RA-FLS. Therefore, TL1A-DcR3/DR3 signaling may be involved in the pathogenesis of RA by modulating apoptosis and proliferation of RA-FLS. We hypothesized that TL1A regulates the gene expression in RA-FLS. We used to search for genes in which expression in RA-FLS is regulated by the ligation of TL1A.
2014-12-10 | GSE63995 | GEO