Ontology highlight
ABSTRACT:
PROVIDER: PRJNA744316 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15056244_1.fastq.gz | Fastqsanger.gz | |||
| SRR15056244_2.fastq.gz | Fastqsanger.gz | |||
| SRR15056245_1.fastq.gz | Fastqsanger.gz | |||
| SRR15056245_2.fastq.gz | Fastqsanger.gz | |||
| SRR15056246_1.fastq.gz | Fastqsanger.gz |
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Project description:Lymphatic endothelial cells (LEC) comprise lymphatic vessels that guide immune cells to lymph nodes (LN) and form the subcapsular sinus and cortical and medullary lymphatic structures of the LN. During an active immune response the lymphatics remodel to accommodate the influx of immune cells from the tissue. In this study we determined that a TSS motif within the cytoplasmic domain of programmed death ligand 1 (PD-L1), expressed by LECs in the LN, participates in lymphatic remodeling during inflammation. Mutation of the TSS motif to AAA in the cytoplasmic domain of PD-L1 does not affect surface expression of PD-L1 but instead causes defects in LN cortical and medullary lymphatic organization following Poly I:C in vivo. Supporting this observation, in vitro treatment of the LEC cell line, SVEC4-10, with the cytokines TNF alpha and IFN alpha significantly impeded SVEC4-10 movement in the presence of the TSS-AAA cytoplasmic mutation. The cellular movement defects coincided with reduced F-actin polymerization, consistent with differences previously found in dendritic cells. Here, in addition to loss of actin polymerization we define STAT3 and Paxillin as important binding partners to PD-L1. STAT3 and Paxillin were previously demonstrated to be important at focal adhesions for cellular motility. We further demonstrate the TSS-AAA motif mutation of PD-L1 reduced the amount of pSTAT3 and Paxillin bound to PD-L1 both before and after exposure to TNF alpha and IFN alpha. Together, these findings highlight PD-L1 as an important component of a membrane complex that is involved in cellular motility which leads to defects in lymphatic organization.
2022-06-01 | MSV000089579 | MassIVE
Project description:G-protein coupled receptors (GPCRs) have diverse roles in physiological processes, including immunity. Gs-coupled GPCRs increase while Gi-coupled ones decrease intracellular cAMP. Previous studies suggest that, in epithelial cells, Gs-coupled GPCRs enhance whereas Gi-coupled GPCRs suppress pro-inflammatory immune responses. In order to examine the issue, we chose beta2 adrenergic receptor and GPR40 as representatives of Gs- and Gi- coupled GPCRs, respectively, and examined their effects on TNF-alpha and IFN-gamma-(TNF-alpha + IFN-gamma) induced gene expression by HaCaT. We used microarrays to detail the global changes of gene expression induced by a beta2 adrenergic receptor agonist terbutaline or GPR40 agonist GW9508 pre-treatment in TNF-alpha + IFN-gamma - stimulated HaCaT cells. HaCaT cells were pre-treated with terbutaline or GW9508, TNF-alpha + IFN-gamma were then added, and cultured for another 24 h. Cells were then used for RNA extraction and hybridization on Affymetrix microarrays. We sought to clarify changes in gene expression after 1) TNF-alpha + IFN-gamma, 2) TNF-alpha + IFN-gamma + terbutaline, and 3) TNF-alpha + IFN-gamma + GW9508 treatment. To this end, we set 4 groups of samples; 1) unstimulated group, 2) TNF-alpha + IFN-gamma-stimulated group, 3) TNF-alpha + IFN-gamma + terbutaline-stimulated group, and 4) TNF-alpha + IFN-gamma + GW9508-stimulated group. In each group, HaCaT cells were stimulated in triplicate wells (n=3).
2010-12-01 | E-GEOD-20297 | biostudies-arrayexpress
Project description:PD-L1 suppresses host immunity and promotes tumor growth. We investigated how IFN-γ regulates PD-L1 in the ovarian cancer microenvironment. In clinical samples, the number of stromal CTLs in peritoneally disseminated tumors was correlated with PD-L1 expression on the tumor cells, and the lymphocyte number was significantly related to the IFN-γ signature score. In mouse models, PD-L1 was induced in peritoneal disseminated tumors, where lymphocytes were prominent, but not in subcutaneous tumors. Depleting IFNGR1 resulted in lower PD-L1 expression and longer survival in peritoneal dissemination model. Injection of IFN-γ into subcutaneous tumors increased PD-L1 expression and tumor size, and PD-L1 depletion abrogated tumor growth. These data suggest that IFN-γ works as a tumor progressor through PD-L1 induction. The source of IFN-γ in ovarian cancer microenvironment and its biological effect to the tumor cells is unclear. The immortalized human ovarian surface epithelial cell line, HOSE-E7/hTERT (HOSE) was treated with IFN-γ and expression microarray analysis was performed, and probes showing significantly higher values in IFN-γ-added group were termed “IFN-γ signature genes (295 probes)”. We then applied this signature to our ovarian cancer microarray data, which included 75 ovarian cancer clinical samples, by means of ss-GSEA. IFN-γ signature score was strongly correlated to the number of infiltrating CD4-positive or CD8-positive lymphocytes in the tumors. These data suggest that the IFN-γ in the ovarian cancer microenvironment is derived from lymphocytes, and an IFN-γ-rich microenvironment is strongly correlated to a lymphocyte-rich microenvironment.
2014-03-04 | GSE55512 | GEO
Project description:We have previously reported that the dengue virus (DENV) type 3 P12/08 strain caused a lethal systemic infection, severe vascular leakage at terminal stage in IFN-α/β and γ receptors knockout mice (IFN-α/β/γRKO mice), and blockade of TNF-α signaling drastically protected mice. However, the detailed pathological mechanism remains unknown. Therefore, we performed transcriptome analysis of liver and intestinal specimens, which showed most clearly exhibited vascular leakage, chronologically collected from infected- IFN-α/β/γRKO mice with/without anti-TNF-α Ab treatment.
2023-11-08 | GSE199821 | GEO
Project description:Background and Aims: Chronic hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) and is a serious health problem in China, East Asia, and North African countries. Effective treatment of HBV-related HCC is currently unavailable. This study evaluated the therapeutic potential of TIGIT blockade in HBV-related HCC. Approach and Results: A mouse model of spontaneous HBV-related HCC was generated by replacing wild-type hepatocytes with HBsAg+ hepatocytes (namely HBs-HepR mice). The tumors in HBs-HepR mice were inflammation-associated HCC, similar to HBV-related HCC in patients, which was distinguished from other HCC mouse models, such as diethylnitrosamine (DEN)-induced HCC, Tak1-knockout-induced HCC, HCC in stelic animal model (STAM), or nonalcoholic steatohepatitis (NASH)-induced HCC. HCC in HBs-HepR mice was characterized by an increased number of CD8+T cells whereas the production of IL-2, TNF-α, and IFN-γ by intrahepatic CD8+T cells was decreased. Increased expression of TIGIT on CD8+T cells was responsible for functional exhaustion. The therapeutic effect of TIGIT blockade was investigated at the early and middle stages of HCC progression in HBs-HepR mice. TIGIT blockade reinvigorated intrahepatic CD8+T cells with increased TNF-α and IFN-γ production and an increased number of CD8+T cells in tumors, thereby slowing the development of HCC in HBs-HepR mice. Blocking PD-L1 did not show direct therapeutic effects or synergize with TIGIT blockade. Conclusions: Blockade of TIGIT alone enhanced the anti-tumor activity of CD8+T cells during the progression of HBV-related HCC in a spontaneous HCC mouse model.
2022-12-31 | GSE209856 | GEO
Project description:Transcriptional response of KBM7 cells to IFN-gamma or TNF-alpha was investigated in control or cells with genetrap insertions in JAK2 or TNFRS1A, respectively. The experiment shows that, as expected, cells lacking JAK2 or TNFRS1A expression display a severly blunted response to the tested cytokines. KBM7 genetrap mutant cells stimulated with TNF-alpha and IFN-gamma Sample WT_1 corresponds with the control sample for the IFN-gamma stimulation; Sample WT_2 corresponds with the control sample for the TNF-alpha stimulation. As the expected differences between the samples was large, only single replicates were performed for each condition
2013-08-09 | E-GEOD-48848 | biostudies-arrayexpress
Project description:COVID-19 has rapidly circulated around the globe and caused significant morbidity and mortality. The disease is characterized by excessive production of pro-inflammatory cytokines and acute lung damage and patient mortality. Although initial cytokine cascades may be beneficial to the host for clearing the virus, enhanced production of pro-inflammatory cytokines and increasing levels in the systemic circulation, referred to as cytokine storm, can promote tissue damage by inducing inflammatory cell death in both infected and bystander cells. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combination of TNF-α and IFN-γ specifically induced cell death characterized by GSDME¬–mediated pyroptosis, caspase-8–mediated apoptosis, and MLKL–mediated necroptosis. Cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. However, deletion of pyroptosis, apoptosis, or necroptosis individually was not sufficient to protect against cell death. Mechanistically, the STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of inflammatory cell death protected mice from TNF-α and IFN-γ–induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. To determine the physiological relevance of protection, we neutralized both TNF-α and IFN-γ in multiple disease models associated with cytokine storm and found that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models. Collectively, our findings reveal that blocking the COVID-19 cytokine-mediated inflammatory cell death signaling pathway identified in this study may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancer where TNF-α and IFN-γ synergism play key pathological roles.
2020-12-03 | GSE160163 | GEO
Project description:The effects of terbutaline or GW9508 on TNF-alpha and IFN gamma (TNF-alpha + IFN gamma) stimulation by HaCaT
| PRJNA125329 | ENA
Project description:Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-g) and tumor necrosis factor alpha (TNF-a), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-a and IFN-g stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-g and TNF-a was synergistic and induced a transcriptome most similar to that found in MSCs stimulation with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-g and TNF-a polarized uniformly to this phenotype. The combination of IFN-g and TNF-a results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-g and TNF-a released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment.
2017-02-09 | GSE77814 | GEO
Project description:Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more significantly in immunocompetent mice. p-AMPKα facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK-STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which may result from nPD-L1-increased MHC-I expression and sensitivity of tumor cells to IFN-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.
2024-11-20 | GSE276400 | GEO