Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Human cancer cells have specifically lost the ability to induce the synergistic state caused by tumor necrosis factor plus interferon-beta.

ABSTRACT: Tumor necrosis factor (TNF) and the members of the interferon (IFN) family are major inducible cytokines that function to counteract viral infections or cellular transformation. Recently, our lab has characterized a novel antiviral state which is induced in primary human fibroblasts by co-treatment with TNF plus IFNbeta. Here, we demonstrate that this synergistic state is both antiviral and cytostatic for primary human cells. Significantly, we observed that a wide spectrum of transformed human cancer cells have universally lost the ability to induce the TNF/IFNbeta synergistic state, as defined by three separate criteria. We hypothesize that the ability to induce the TNF/IFNbeta synergistic state is a unique feature of primary cells and is incompatible with cellular immortalization and/or transformation.

SUBMITTER: Bartee E

PROVIDER: S-EPMC4376283 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Human cancer cells have specifically lost the ability to induce the synergistic state caused by tumor necrosis factor plus interferon-beta.

Bartee Eric E McFadden Grant G

Cytokine 20090728 3

Tumor necrosis factor (TNF) and the members of the interferon (IFN) family are major inducible cytokines that function to counteract viral infections or cellular transformation. Recently, our lab has characterized a novel antiviral state which is induced in primary human fibroblasts by co-treatment with TNF plus IFNbeta. Here, we demonstrate that this synergistic state is both antiviral and cytostatic for primary human cells. Significantly, we observed that a wide spectrum of transformed human c ...[more]

PMID: 19640730

Similar Datasets

The addition of tumor necrosis factor plus beta interferon induces a novel synergistic antiviral state against poxviruses in primary human fibroblasts.

Project description:Tumor necrosis factor (TNF) and members of the interferon (IFN) family have been shown to independently inhibit the replication of a variety of viruses. In addition, previous reports have shown that treatment with various combinations of these antiviral cytokines induces a synergistic antiviral state that can be significantly more potent than addition of any of these cytokines alone. The mechanism of this cytokine synergy and its effects on global gene expression, however, are not well characterized. Here, we use DNA microarray analysis to demonstrate that treatment of uninfected primary human fibroblasts with TNF plus IFN-beta induces a distinct synergistic state characterized by significant perturbations of several hundred genes which are coinduced by the individual cytokines alone, as well as the induction of more than 850 novel host cell genes. This synergy is mediated directly by the two ligands, not by intermediate secreted factors, and is necessary and sufficient to completely block the productive replication and spread of myxoma virus in human fibroblasts. In contrast, the replication of two other poxviruses, vaccinia virus and tanapox virus, are only partially inhibited in these cells by the synergistic antiviral state, whereas the spread of both of these viruses to neighboring cells was efficiently blocked. Taken together, our data indicate that the combination of TNF and IFN-beta induces a novel synergistic antiviral state that is highly distinct from that induced by either cytokine alone.

| S-EPMC2612348 | biostudies-literature

Cytokines tumor necrosis factor-? and interferon-? induce pancreatic ?-cell apoptosis through STAT1-mediated Bim protein activation.

Project description:Type 1 diabetes is characterized by local inflammation (insulitis) in the pancreatic islets causing ?-cell loss. The mitochondrial pathway of apoptosis is regulated by the balance and interaction between Bcl-2 members. Here we clarify the molecular mechanism of ?-cell death triggered by the pro-inflammatory cytokines tumor necrosis factor (TNF)-? and interferon (IFN)-?. The combination of TNF-? + IFN-? induced DP5, p53 up-regulated modulator of apoptosis (PUMA), and Bim expression in human islets and rodent ?-cells. DP5 and PUMA inactivation by RNA interference partially protected against TNF-? + IFN-?-induced ?-cell apoptosis. DP5 knock-out mice had increased ?-cell area, and isolated islets from these mice were resistant to cytokine exposure. Bim expression was transcriptionally regulated by STAT1, and its activation triggered cleavage of caspases. Silencing of Bim protected rodent and human ?-cells to a large extent against TNF-? + IFN-?, indicating a major role of this BH3-only activator protein in the mechanism of apoptosis. Our data support a highly regulated and context-dependent modulation of specific Bcl-2 members controlling the mitochondrial pathway of ?-cell apoptosis during insulitis.

| S-EPMC3234786 | biostudies-literature

Silybin supplementation during HCV therapy with pegylated interferon-? plus ribavirin reduces depression and anxiety and increases work ability.

Project description:Hepatitis C virus infection and interferon treatment are often associated with anxiety, depressive symptoms and poor health-related quality of life. To evaluate the Silybin-vitamin E-phospholipids complex effect on work ability and whether health related factors (anxiety and depression) were associated with work ability in subjects with chronic hepatitis C treated with Pegylated-Interferon-?2b (Peg-IFN) and Ribavirin (RBV).Thirty-one patients (Group A) with chronic hepatitis and other 31 subjects in Group B were recruited in a randomized, prospective, placebo controlled, double blind clinical trial. Group A received 1.5 mg/kg per week of Peg-IFN plus RBV and placebo, while Group B received the same dosage of Peg-IFN plus RBV plus association of Silybin 94 mg?+?vitamin E 30 mg?+?phospholipids 194 mg in pills for 12 months. All subjects underwent to laboratory exams and questionnaires to evaluate depression (Beck Depression Inventory - BDI), anxiety (State-trait anxiety inventory - STAI) and work ability (Work ability Index - WAI).The comparison between group A and group B showed significant differences after 6 months in ALT (P?<?0.001), and viremia (P?<?0.05), after 12 months in ALT (P?<?0.001), and AST (P?<?0.001), at follow up in AST (P?<?0.05), and ALT (P?<?0.001). Significant difference were observed after 1 month in WAI (p?<?0.001) and BDI (P?<?0.05), after 6 months in WAI (P?<?0.05) and STAI (P?<?0.05), after 12 months and at follow up in WAI, STAI and BDI (p?<?0.01).The supplementation with Silybin-vitamin E -phospholipids complex increased work ability and reduced depression and anxiety in patients treated with Peg-IFN and RBV.NCT01957319 , First received: September 25, 2013. Last updated: September 30, 2013 (retrospectively registered).

| S-EPMC5109776 | biostudies-literature

C/EBPbeta mediates synergistic upregulation of gene expression by interferon-gamma and tumor necrosis factor-alpha in bone marrow-derived mesenchymal stem cells.

Project description:Mesenchymal stem cells (MSCs) are potent immunoregulators and have shown clinical utility in suppressing immunity. MSC function is modulated by cytokines, since inflammatory cytokines, such as interferon-gamma (IFNgamma) concomitant with tumor necrosis factor-alpha (TNFalpha), induce their immunoregulatory capability. Here, we show that IFNgamma and TNFalpha act synergistically to induce high levels of expression of interleukin-6 (IL-6) and several other immune-related molecules in MSCs in vitro. We further found that, while either IFNgamma or TNFalpha alone induced minor expression of C/EBPbeta in MSCs, this transcription factor was dramatically upregulated when these cytokines were added together. A causal relationship between C/EBPbeta upregulation and IL-6 expression was demonstrated by small interfering RNA knockdown of C/EBPbeta. C/EBPbeta knockdown also inhibited the synergistic expression of CXCL1, inducible nitric oxide synthase, and CCL5 in response to concomitant IFNgamma and TNFalpha. We conclude that C/EBPbeta is a key transcription factor in synergistic gene upregulation by IFNgamma and TNFalpha. Importantly, C/EBPbeta similarly mediated synergistic gene induction in response to IFNgamma accompanied by IL-1beta or lipopolysaccharide, suggesting that synergy between IFNgamma and other stimuli share C/EBPbeta as common mechanism. Furthermore, while STAT1 is critical in IFNgamma signaling, we found that STAT1 knockdown in MSCs did not affect C/EBPbeta expression or the synergistic induction of IL-6 and CXCL1 by IFNgamma and TNFalpha. Thus, C/EBPbeta is not regulated by STAT1. These results demonstrate the importance of cytokine interactions in MSC immunobiology, a better understanding of which will allow improved clinical application of these cells.

| S-EPMC3412173 | biostudies-literature

Interferon-gamma and tumor necrosis factor-alpha induce an immunoinhibitory molecule, B7-H1, via nuclear factor-kappaB activation in blasts in myelodysplastic syndromes.

Project description:During disease progression in myelodysplastic syndromes (MDS), clonal blasts gain a more aggressive nature, whereas nonclonal immune cells become less efficient via an unknown mechanism. Using MDS cell lines and patient samples, we showed that the expression of an immunoinhibitory molecule, B7-H1 (CD274), was induced by interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) on MDS blasts. This induction was associated with the activation of nuclear factor-kappaB (NF-kappaB) and nearly completely blocked by an NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC). B7-H1(+) MDS blasts had greater intrinsic proliferative capacity than B7-H1(-) MDS blasts when examined in various assays. Furthermore, B7-H1(+) blasts suppressed T-cell proliferation and induced T-cell apoptosis in allogeneic cocultures. When fresh bone marrow samples from patients were examined, blasts from high-risk MDS patients expressed B7-H1 molecules more often compared with those from low-risk MDS patients. Moreover, MDS T cells often overexpressed programmed cell death 1 (PD-1) molecules that transmit an inhibitory signal from B7-H1 molecules. Taken together, these findings provide new insight into MDS pathophysiology. IFNgamma and TNFalpha activate NF-kappaB that in turn induces B7-H1 expression on MDS blasts. B7-H1(+) MDS blasts have an intrinsic proliferative advantage and induce T-cell suppression, which may be associated with disease progression in MDS.

| S-EPMC3375140 | biostudies-literature

Synergistic interactions with PI3K inhibition that induce apoptosis.

Project description:Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition.

| S-EPMC5479695 | biostudies-literature

Aggregation State of Synergistic Antimicrobial Peptides.

Project description:By integrating various simulation and experimental techniques, we discovered that antimicrobial peptides (AMPs) may achieve synergy at an optimal concentration and ratio, which can be caused by aggregation of the synergistic peptides. On multiple time and length scales, our studies obtain novel evidence of how peptide coaggregation in solution can affect the disruption of membranes by synergistic AMPs. Our findings provide crucial details about the complex molecular origins of AMP synergy, which will help guide the future development of synergistic AMPs as well as applications of anti-infective peptide cocktail therapies.

| S-EPMC8299379 | biostudies-literature

Single-nucleotide methylation specifically represses type I interferon in antiviral innate immunity.

Project description:Frequent outbreaks of viruses have caused a serious threat to public health. Previous evidence has revealed that DNA methylation is correlated with viral infections, but its role in innate immunity remains poorly investigated. Additionally, DNA methylation inhibitors promote IFN-I by upregulating endogenous retrovirus; however, studies of intrinsically demethylated tumors do not support this conclusion. This study found that Uhrf1 deficiency in myeloid cells significantly upregulated Ifnb expression, increasing resistance to viral infection. We performed whole-genome bisulfite sequencing and found that a single-nucleotide methylation site in the Ifnb promoter region disrupted IRF3 recruitment. We used site-specific mutant knock-in mice and a region-specific demethylation tool to confirm that this methylated site plays a critical role in regulating Ifnb expression and antiviral responses. These findings provide essential insight into DNA methylation in the regulation of the innate antiviral immune response.

| S-EPMC7903198 | biostudies-literature

The Architect Who Lost the Ability to Imagine: The Cerebral Basis of Visual Imagery.

Project description:While the loss of mental imagery following brain lesions was first described more than a century ago, the key cerebral areas involved remain elusive. Here we report neuropsychological data from an architect (PL518) who lost his ability for visual imagery following a bilateral posterior cerebral artery (PCA) stroke. We compare his profile to three other patients with bilateral PCA stroke and another architect with a large PCA lesion confined to the right hemisphere. We also compare structural images of their lesions, aiming to delineate cerebral areas selectively lesioned in acquired aphantasia. When comparing the neuropsychological profile and structural magnetic resonance imaging (MRI) for the aphantasic architect PL518 to patients with either a comparable background (an architect) or bilateral PCA lesions, we find: (1) there is a large overlap of cognitive deficits between patients, with the very notable exception of aphantasia which only occurs in PL518, and (2) there is large overlap of the patients' lesions. The only areas of selective lesion in PL518 is a small patch in the left fusiform gyrus as well as part of the right lingual gyrus. We suggest that these areas, and perhaps in particular the region in the left fusiform gyrus, play an important role in the cerebral network involved in visual imagery.

| S-EPMC7071355 | biostudies-literature

The lost ability to distinguish between self and other voice following a brain lesion.

Project description:Mechanisms underlying the self/other distinction have been mainly investigated focusing on visual, tactile or proprioceptive cues, whereas very little is known about the contribution of acoustical information. Here the ability to distinguish between self and others' voice is investigated by using a neuropsychological approach. Right (RBD) and left brain damaged (LBD) patients and healthy controls were submitted to a voice discrimination and a voice recognition task. Stimuli were paired words/pseudowords pronounced by the participant, by a familiar or unfamiliar person. In the voice discrimination task, participants had to judge whether two voices were same or different, whereas in the voice recognition task participants had to judge whether their own voice was or was not present. Crucially, differences between patient groups were found. In the discrimination task, only RBD patients were selectively impaired when their own voice was present. By contrast, in the recognition task, both RBD and LBD patients were impaired and showed two different biases: RBD patients misattributed the other's voice to themselves, while LBD patients denied the ownership of their own voice. Thus, two kinds of bias can affect self-voice recognition: we can refuse self-stimuli (voice disownership), or we can misidentify others' stimuli as our own (embodiment of others' voice). Overall, these findings reflect different impairments in self/other distinction both at behavioral and anatomical level, the right hemisphere being involved in voice discrimination and both hemispheres in the voice identity explicit recognition. The finding of selective brain networks dedicated to processing one's own voice demonstrates the relevance of self-related acoustic information in bodily self-representation.

| S-EPMC5988014 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data