TNF activates a distinct cellular program in human regulatory T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE18893 | GEO | 2009/12/31
SECONDARY ACCESSION(S): PRJNA121295
REPOSITORIES: GEO
Similar Datasets
Project description:Persistent NF-κB activation is a hallmark of the malignant Hodgkin/Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL). Analysis of the cHL cell-secreted key factors for NF-κB activation by chromatography and subsequent mass spectrometry revealed lymphotoxin-α (LTA) as the causative factor for autocrine and paracrine activation of canonical and noncanonical NF-κB in cHL cell lines. Upon CRISPR/Cas9-mediated gene knockout of LTA in the cell line L-1236, we performed expression analysis of LTA knockout versus control cells by using the Affymetrix array, Clariom S human, profiling tool.
2019-05-22 | GSE131559 | GEO
Project description:TNF is a key inflammatory cytokine that warns recipient cells of a nearby infection or tissue damage. Acute exposure to TNF activates characteristic oscillatory dynamics of the transcription factor NFκB and induces a characteristic gene expression program; these are distinct from the responses of cells directly exposed to pathogen-associated molecular patterns (PAMPs). Here we report that tonic TNF exposure is critical for safeguarding TNF’s specific functions. In the absence of tonic TNF conditioning, acute exposure to TNF causes 1) NFκB signaling dynamics that are less oscillatory and more like PAMP-responsive NFκB dynamics, 2) immune gene expression that is more similar to the Pam3CSK4-response program, 3) broader epigenomic reprogramming that is characteristic of PAMP-responsive changes. We show that tonic TNF signaling effects subtle changes to TNF receptor availability and dynamics such that enhanced pathway activity results in non-oscillatory NFκB. Our results reveal tonic TNF signaling as a key tissue determinant of the specific characteristics of cellular responses to acute paracrine TNF exposure, and their distinction from responses to direct exposure to PAMPs.
2022-07-27 | GSE209565 | GEO
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:Activated Foxp3+ regulatory T cells (Tregs) express several TNF receptor superfamily (TNFRSF) members. Here, we analyzed the transcriptome of purified Tregs that were activated with anti-CD3 and anti-CD28 mAbs, IL-2 and with or without agonists of TNFR2, 4-1BB, DR3 and OX40 for 18h and 36h. Triggering these TNFRSF in Tregs induces similar changes in gene expression patterns, suggesting that they engage common signal transduction pathways. Among them, we identified a major role of canonical NF-κB.
2020-04-01 | GSE146135 | GEO
Project description:Determination of absolute abundance of TNF-RSC members in the isolated TNF-RSC.
2022-10-13 | PXD019879 | Pride
Project description:Stringent regulation of TNF signaling prevents aberrant inflammation. TNF engages the canonical NF-kB pathway for activating the RelA:p50 heterodimer, which mediates specific expressions of pro-inflammatory and immune response genes. Importantly, the NF-kB system discriminates between time-varied TNF inputs. Negative feedback regulators of the canonical pathway, including IkBa, thought to ensure transient RelA:p50 responses to brief TNF stimulations. The noncanonical NF-kB pathway controls a separate RelB activity associated with immune differentiation. In a systems modeling approach, we uncovered an unexpected role of p100, a constituent of the noncanonical pathway, in TNF signaling. Brief TNF stimulation of p100-deficient cells produced an additional late NF-kB activity composed of the RelB:p50 heterodimer, which distorted the TNF-induced gene-expression program. Periodic TNF pulses augmented this RelB:p50 activity, which was reinforced by NF-kB-dependent RelB synthesis. In sum, the NF-kB system seems to engage distantly related molecular species for enforcing dynamical and gene controls of immune-activating TNF signaling.
2020-08-22 | GSE119961 | GEO
Project description:Rationale: Endothelial cells (ECs) line the inner surface of continuous capillaries and form a permselective barrier between blood and tissues to limit paracellular fluid and solute flux. The capillary barrier is maintained by intercellular tight junctions (TJs) which are regulated, in part, by differential activity of small GTPases. Tumor necrosis factor (TNF) causes TJ disassembly in a process dependent upon NF-κB-mediated gene expression. Activated (GTP-bound) RhoB has been identified as a downstream effector of TNF-induced leak both through Rho-associated coiled-coil kinase-mediated phosphorylation of RelA, enhancing TNF-induced NF-κB-mediated gene activation, and through sequestration of Rac1 away from the cell junction, preventing barrier restoration. To date, no TNF-induced, RhoB-selective GTP exchange factor (GEF) has been identified in ECs. Objective: Identify a TNF-induced RhoB specific GEF in capillary ECs. Method and Results: human dermal microvascular ECs (HDMECs) were used because they form TJs. Candidate GEFs were identified by whole transcriptome profiling of HDMECs with or without TNF stimulation. Fifty-seven of 73 known GEFs were expressed in HDMECs and 17 were significantly upregulated by TNF. Functional impact of each of the latter group was assessed by measuring the effects of depletion by short interfering RNA knockdown on TNF-induced reduction of trans-endothelial electrical resistance (TEER) of HDMEC monolayers. Depletions of ArhGEF10 or RhoB or double depletion of ArhGEF10/RhoB similarly decreased TNF-mediated reduction of TEER. ArhGEF10 knockdown prevented TNF-induced disruption of TJ proteins assessed by confocal microscopy. TNF-induced increases in the levels of activated RhoB in HDMEC lysates were markedly reduced with only minimal alterations in RhoA or RhoC activation. Finally, immunoisolated ArhGEF10 selectively catalyzed GTP exchange for GDP in RhoB, but not RhoA or RhoC, in vitro. Conclusion: ArhGEF10 is a TNF-induced RhoB-selective GEF for RhoB in cultured human capillary ECs that contributes to TJ disruption.
2021-05-10 | GSE161021 | GEO
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:Comparison of the immune response of human whole blood to lipoteichoic acid (LTA) derived from the Staphylococcus aureus SA113 delta-lgt mutant (lacks lipoproteins), LTA from S. aureus SA113 wt. and PAM2Cys, a lipoprotein analogue. Background: Our goal was to expand our report that LTA from SA 113 wildtype (wt LTA) and delta-lgt (lgt LTA) induce equal amounts of TNF release by human whole blood (von Aulock et al., J Immunol, 2007). Therefore we traced the translational activation by both LTA in comparison to the synthetic diacylated lipoprotein Pam2Cys-SK4 in human whole blood on an immunology microarray comprising 1076 genes related to apoptosis and signal transduction, cell cycle, chemokines, cytokines and their receptors, extracellular matrix proteins, inflammation and complement system. Results and Discussion: The results show extensive overlaps of the clustered heat-maps of SA113 wt and lgt LTA, which are clearly different from those of Pam2Cys-SK4 stimulation. Only four of the 1076 genes were significantly differently regulated after stimulation with the LTAs, whereas stimulation with Pam2Cys-SK4 led to a significantly different regulation of 43 genes compared to SA 113 wt LTA and 39 compared to SA 113 lgt LTA. Mainly chemokines were upregulated by both LTA, which is consistent with our previous findings (von Aulock et al., Immunobiol, 2003) and different from stimulations with Pam2Cys-SK4. The gene array results support our protein data obtained from LTA-stimulated human whole blood and point to a significant concordance between the immunostimulatory activity of lgt and wt LTA preparations. In contrast, a distinct difference is observed between both LTA and the synthetic lipoprotein Pam2Cys-SK4. This supports the conclusion that the immunostimulatory activity of wt LTA in human whole blood is not determined by possible lipoprotein contaminations.
2015-04-05 | GSE21188 | GEO
Project description:TNF plays a key role in inflammation and bone resorption. However, the mechanisms regulating TNF-mediated osteoclastogenesis remain largely unclear because its direct osteoclastogenic ability is weak. Here, we found that TGFβ priming enables TNF to effectively induce osteoclastogenesis from macrophages, independently of the osteoclastogenic action of RANKL. Lack of TGFβ signaling in macrophages suppresses inflammatory, but not physiological, osteoclastogenesis and bone resorption in vivo. Mechanistically, TGFβ priming reprograms macrophage response to TNF towards osteoclastogenesis by remodeling chromatin accessibility and histone modification. TGFβ and TNF induce an unconventional osteoclastogenic program, which includes the suppression of the TNF-induced IRF1-IFNβ-IFN stimulated gene (ISG) axis, promotion of IRF8 degradation and B-Myb induction. These mechanisms are present in RA, in which TGFβ level is elevated and correlated with osteoclast activity. Our findings identify a function and mechanism of action for TGFβ in TNF-mediated inflammatory osteoclastogenesis, and open avenues for selective treatment of inflammatory bone loss.
2022-03-24 | GSE171842 | GEO