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BID is critical for IFN-alpha-induced cell death

ABSTRACT: Clinical applications of human interferon (IFN)-alpha have met with varying degrees of success. Nevertheless, key molecules in IFN-alpha-induced cell death have not been clearly identified. Our previous study indicated that IFN (alpha, beta and omega) receptor (IFNAR) 1/2- and IFN regulatory factor (IRF) 9-RNA interference (RNAi) completely inhibited the antiproliferative (AP) activity of IFN-alpha in human ovarian adenocarcinoma OVCAR3 cells sensitive to IFN-alpha., followed by transcription of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, IFNAR1/2- and IRF9-RNAi inhibited the gene expression of TRAIL, but not of Fas ligand (FasL), following IFN-alpha treatment. In fact, TRAIL but not FasL inhibited the proliferation of OVCAR3 cells. IFN-alpha notably up-regulated the levels of TRAIL protein in the supernatant and on the membrane of OVCAR3 cells. Following TRAIL signaling, Caspase 8 inhibitor and BH3 interacting domain death agonist (BID)-RNAi significantly abrogated both AP activities of IFN-alpha and TRAIL. Furthermore, BID-RNAi prevented both IFN-alpha and TRAIL from collapsing the mitochondrial membrane potential (Delta Psi m). Finally, we provide important new evidence that BID overexpression led to a major enhancement of both AP activities of IFN-alpha and TRAIL in human lung carcinoma A549 cells resistant to IFN-alpha. Thus, this study suggests that BID is crucial in IFN-alpha-induced cell death, indicating a notable potential to be a targeted therapy for IFN-alpha resistant tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE29790 | GEO | 2012/05/22

SECONDARY ACCESSION(S): PRJNA141071

REPOSITORIES: GEO

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BID is critical for IFN-alpha-induced cell death

Project description:Clinical applications of human interferon (IFN)-alpha have met with varying degrees of success. Nevertheless, key molecules in IFN-alpha-induced cell death have not been clearly identified. Our previous study indicated that IFN (alpha, beta and omega) receptor (IFNAR) 1/2- and IFN regulatory factor (IRF) 9-RNA interference (RNAi) completely inhibited the antiproliferative (AP) activity of IFN-alpha in human ovarian adenocarcinoma OVCAR3 cells sensitive to IFN-alpha., followed by transcription of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, IFNAR1/2- and IRF9-RNAi inhibited the gene expression of TRAIL, but not of Fas ligand (FasL), following IFN-alpha treatment. In fact, TRAIL but not FasL inhibited the proliferation of OVCAR3 cells. IFN-alpha notably up-regulated the levels of TRAIL protein in the supernatant and on the membrane of OVCAR3 cells. Following TRAIL signaling, Caspase 8 inhibitor and BH3 interacting domain death agonist (BID)-RNAi significantly abrogated both AP activities of IFN-alpha and TRAIL. Furthermore, BID-RNAi prevented both IFN-alpha and TRAIL from collapsing the mitochondrial membrane potential (Delta Psi m). Finally, we provide important new evidence that BID overexpression led to a major enhancement of both AP activities of IFN-alpha and TRAIL in human lung carcinoma A549 cells resistant to IFN-alpha. Thus, this study suggests that BID is crucial in IFN-alpha-induced cell death, indicating a notable potential to be a targeted therapy for IFN-alpha resistant tumors. Biological replicate samples were created by treating OVCAR3 cells with IFN-alpha2c (n=8); IFNAR1-RNAi and IFN-alpha2c (n=4); IFNAR2-RNAi and IFN-alpha2c (n=5); ISGF3gamma-RNAi and IFN-alpha2c (n=3); and Negative RNAi and IFN-alpha2c (n=3). For analysis, the eight IFN-alpha2c treated OVCAR3 samples were paired with an untreated OVCAR3 control sample. The 15 RNAi treated OVCAR3 samples were paired with a Negative RNAi control sample.

2012-05-21 | E-GEOD-29790 | biostudies-arrayexpress

Homo sapiens

Project description:BID is critical for IFN-alpha-induced cell death

| PRJNA141071 | ENA

Induction of TRAIL and TNF-alpha-dependent Apoptosis in Human mDCs by Microfilariae of Brugia Malayi

Project description:Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that circulates in blood and is responsible for most immune dysregulation in filarial infections. DC exposed to mf for 24–96 h showed a marked increase in cell death and caspase-positive cells compared with unexposed DC, while mf exposure did not induce apoptosis in macrophages. Interestingly, 48 h exposure of DC to mf induced mRNA expression of the pro-apoptotic gene TRAIL and both mRNA and protein expression of TNF-alpha. mAb to TRAIL-R2, TNF-R1, or TNF-alpha partially reversed mf-induced cell death in DC, as did knocking down the receptor for TRAIL-R2 using small interfering RNA. Mf also induced gene expression of BH3-interacting domain death agonist (Bid) and protein expression of cytochrome c in DC; mf-induced cleavage of Bid could be shown to induce release of cytochrome c, leading to activation of caspase 9. Our data suggest that mf induce DC apoptosis in a TRAIL- and TNF-alpha-dependent fashion. Keywords: Dendritic Cell, Parasite, Human, Microfilariae

2008-09-17 | GSE12787 | GEO

Transcription profiling of human dendritic cells exposed to microfilariae of Brugia Malayireveals induction of trail and TNF-alpha-dependent apoptosis

Project description:Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that circulates in blood and is responsible for most immune dysregulation in filarial infections. DC exposed to mf for 24â96 h showed a marked increase in cell death and caspase-positive cells compared with unexposed DC, while mf exposure did not induce apoptosis in macrophages. Interestingly, 48 h exposure of DC to mf induced mRNA expression of the pro-apoptotic gene TRAIL and both mRNA and protein expression of TNF-alpha. mAb to TRAIL-R2, TNF-R1, or TNF-alpha partially reversed mf-induced cell death in DC, as did knocking down the receptor for TRAIL-R2 using small interfering RNA. Mf also induced gene expression of BH3-interacting domain death agonist (Bid) and protein expression of cytochrome c in DC; mf-induced cleavage of Bid could be shown to induce release of cytochrome c, leading to activation of caspase 9. Our data suggest that mf induce DC apoptosis in a TRAIL- and TNF-alpha-dependent fashion. Experiment Overall Design: Microfilariae and human monocyte derived-DCs were cultuted at a multiplicity of infection of 1:1 for 24hrs for four independent donors. Matching samples exposed to media alone were used for controls The four experimental and 4 control samples were then pooled to create one experoimental and one healthy pool used for microarray analysis.

2008-10-25 | E-GEOD-12787 | biostudies-arrayexpress

Acquired resistance of Jurkat cells to TNF-related apoptosis-inducing ligand (TRAIL): a role for histone deacetylase inhibitors as powerful apoptosis sensitizer.

Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be a potent inducer of apoptosis in various cancer cell lines and primary cancer cells. However, in clinical trials administration of recombinant TRAIL or TRAIL death receptor agonists did not show sufficient efficacy for treatment of tested malignant disorders compared to standard chemotherapy. Acquired resistance of cancer cells to TRAIL and to other “death receptor” ligands may explain not only the inability of TRAIL and TRAIL “death receptor” agonists to achieve the clearance of cancer cells in vivo but also the escape of cancer cells from immune cell – mediated killing. Selective pressure of TRAIL on TRAIL-sensitive Jurkat T-lymphoblastic leukemia cells provided several TRAIL resistant Jurkat cell line clones (TR1, TR2, TR3). Irrespective of molecular changes histone deacetylase inhibitors (HDACi), such as suberoylanilide-hydroxamic acid (SAHA, vorinostat), were able to restore sensitivity of all three TRAIL-resistant clones to TRAIL. Gene expression analysis of TR1 clone treated with SAHA 1microM for 12 hours compared to untreated TR1 clone showed significant decrease in expression of CFLAR/cFLIP (0.71; p=0.006), BIRC5/survivin (0.80; p=0.024) and BID (0.66; p<0.001). Expression of both TRAIL “death” receptors DR4 (1.57; p<0.001) and DR5 (1.47; p=0.002) were significantly increased compared to untreated TR1 cells. The mRNA expression of caspases-2,-3,-8,-9,-10 did not significantly change with the SAHA treatment.

2016-06-15 | GSE38745 | GEO

Acquired resistance of Jurkat cells to TNF-related apoptosis-inducing ligand (TRAIL): a role for histone deacetylase inhibitors as powerful apoptosis sensitizer.

Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be a potent inducer of apoptosis in various cancer cell lines and primary cancer cells. However, in clinical trials administration of recombinant TRAIL or TRAIL death receptor agonists did not show sufficient efficacy for treatment of tested malignant disorders compared to standard chemotherapy. Acquired resistance of cancer cells to TRAIL and to other âdeath receptorâ ligands may explain not only the inability of TRAIL and TRAIL âdeath receptorâ agonists to achieve the clearance of cancer cells in vivo but also the escape of cancer cells from immune cell â mediated killing. Selective pressure of TRAIL on TRAIL-sensitive Jurkat T-lymphoblastic leukemia cells provided several TRAIL resistant Jurkat cell line clones (TR1, TR2, TR3). Irrespective of molecular changes histone deacetylase inhibitors (HDACi), such as suberoylanilide-hydroxamic acid (SAHA, vorinostat), were able to restore sensitivity of all three TRAIL-resistant clones to TRAIL. Gene expression analysis of TR1 clone treated with SAHA 1microM for 12 hours compared to untreated TR1 clone showed significant decrease in expression of CFLAR/cFLIP (0.71; p=0.006), BIRC5/survivin (0.80; p=0.024) and BID (0.66; p<0.001). Expression of both TRAIL âdeathâ receptors DR4 (1.57; p<0.001) and DR5 (1.47; p=0.002) were significantly increased compared to untreated TR1 cells. The mRNA expression of caspases-2,-3,-8,-9,-10 did not significantly change with the SAHA treatment. Total cellular RNA was isolated from biologic duplicates of untreated Jurkat cells (WT), TRAIL resistant Jurkat cell clone (TR1) and 1 ÂµM and 0.5 ÂµM suberoylanilide-hydroxamic acid (SAHA, vorinostat) treated TR1 cell clones for 12 hours. Jurkat cell line subclones TR1was established by selective pressure of TRAIL 1000 ng/mL on Jurkat cells over the period of 12 weeks.

2016-06-15 | E-GEOD-38745 | biostudies-arrayexpress

Proteomic analysis of TRAIL-induced endogenous RIPK3-dependent necrosome complex

Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a well-known inducer of apoptosis via formation of the primary death-inducing signaling complex (TRAIL-DISC) at the level of membrane death receptors (DR4 and DR5) which recruit successively FADD and caspase-8. TRAIL can also induce necroptosis when caspases are inhibited. Necroptosis is a regulated cell death dependent on the formation of a cytosolic necrosome complex which includes RIPK1, RIPK3 and MLKL proteins. Elucidating the molecular mechanisms involved in TRAIL-induced necroptosis might provide new insights into the TRAIL death signaling pathway. Here, we report the analysis by mass spectrometry of endogenous RIPK3-dependent necrosome complex constituents upon necroptosis induced by TRAIL/z-VAD/Birinapant (TzB) in HT29 cells. Besides characterization of RIPK1, RIPK3, MLKL, FADD, caspase-8, we find TRIM21 as a new constituent of the necrosome complex. Moreover RIPK1, RIPK3, MLKL, P-MLKL, FADD, caspase-8 and TRIM21 are also found associated to the native TRAIL-DISC upon TzB stimulation showing initiation of the necrotic pathway at the level of TRAIL death receptors in HT29 cells. Finally, TRIM21 may positively modulate necroptosis induction by downregulating NF-kB activation.

2021-03-18 | PXD003383 | Pride

Gene expression data from murine CAR T cells

Project description:Compare the gene expression profile among Mouse m19delta.GFP and m1928z.GFP T cells and examine the differential upregulation of Bim, Bid, FasL and Apaf1 in m1928z T cells.

2017-01-05 | GSE85397 | GEO

Transcription profiling of human endothelial and fibroblast cells isolated from umbilical cord veins treated with interferons to identify genes regulated by interferons

Project description:IFNs are highly pleiotropic cytokines also endowed with marked anti-angiogenic activity. In this study, the mRNA expression profiles of endothelial cells (EC) exposed in vitro to IFN-alpha, IFN-beta, or; IFN-gamma were determined. We found that in HUVEC as well as in other EC types 175 genes were upregulated (>2-fold increase) by IFNs, including genes involved in the host response to RNA viruses, inflammation, and apoptosis. Interestingly, 41 genes showed a >5-fold higher induction by IFN-alpha in EC compared to human fibroblasts; among them, the gene encoding the angiostatic chemokine CXCL11 was selectively induced by IFN-alpha in EC along with other genes associated; with angiogenesis regulation, including CXCL10, TRAIL, and guanylate binding protein 1 (GBP-1). These transcriptional changes were confirmed and extended by quantitative PCR analysis and ELISA; whereas IFN-alpha and IFN-beta exerted virtually identical effects on transcriptome modulation, a differential gene regulation by type I and type II IFN emerged, especially as far as quantitative aspects were concerned. In vivo, IFN-alpha-producing tumors over-expressed murine CXCL10-11,; GBP-1 and TRAIL, with evidence of CXCL11 production by tumor-associated EC. Overall, these findings improve our understanding of the anti-angiogenic effects of IFNs by showing that these cytokines trigger an anti-angiogenic transcriptional program in EC. Moreover, we suggest that quantitative differences in the magnitude of the transcriptional activation of IFNresponsive genes could form the basis for cell-specific transcriptional signatures. In press, J. Immunol. 2007. Experiment Overall Design: comparison of interferon effects on endothelial cells (HUVEC, HMVEC) and fibrobloasts

2009-04-08 | E-GEOD-3920 | biostudies-arrayexpress

Gene expression changes in breast epithelial cells surviving treatment with TRAIL (TNF-Related Apoptosis Inducing Ligand)

Project description:In this study, we subjected the phenomenon of fractional killing in a clonal population of TRAIL-sensitive cells to careful analysis. We asked whether cells that survive initial exposure to TRAIL are sensitive or resistant to subsequent treatment with TRAIL or other apoptosis-inducing agents. We observed that TRAIL survivor cells were highly resistant to a subsequent treatment with TRAIL 24hr later but that this resistance disappeared following several days in culture. Resistance did not involve downregulation of TRAIL receptors and extended to death ligands that bind different classes of receptors: TRAIL survivors were transiently resistant to FasL and vice versa. Gene expression analysis revealed that NF-kB-mediated inflammatory genes were activated in transiently resistant survivor cells leading to an inflammatory phenotype, but resistance was mediated by an independent mechanism related to changes in signaling at the DISC. Periodic exposure to TRAIL sustained resistance, demonstrating a component of induced survival signaling leading to transient acquired resistance to TRAIL. Based on these results we propose that TRAIL treatment leads to a transient adaptation in survivor cells that can be sustained in cells exposed to long-term TRAIL treatments, leading to acquired resistance. Minimizing the impact of cell-to-cell variability on TRAIL-mediated killing will thus require appropriate spacing of stimuli as well as the use of additional agents that inhibit pro-survival pathways.

2013-07-15 | GSE33340 | GEO

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