Interferon‐induced TRAIL‐independent cell death in <i>DNase II<sup>−/−</sup></i> embryos

Kitahara, Yusuke; Kawane, Kohki; Nagata, Shinji

doi:10.1002/eji.201040604

Cited by 8 publications

(12 citation statements)

References 40 publications

(48 reference statements)

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“…It was suggested previously that increased caspase-8 and decreased cFLIP levels are sufficient to induce apoptosis independent of death ligands (38,39). Examination of the relative amounts of caspase-8 upon interferon treatment showed an increase in caspase-8 protein levels from 8 h onwards, reaching a maximum of ϳ4-fold the basal level at 48 h (Fig.…”

Section: Ifn-induced Apoptosis Is Death Ligand Independentmentioning

confidence: 61%

“…Several previous studies reported apoptosis induction by cFLIP silencing on the DISC, without the involvement of an external ligand (38,39). Of particular interest is previous work by Wilson et al (39), who demonstrated that a higher expression level of procaspase-8 or silencing of cFLIP is sufficient to induce apoptosis with an involvement of the DR5 receptor but without external death ligand.…”

Section: Discussionmentioning

confidence: 96%

“…The mechanism of how the JAK-STAT pathway leads to caspase activation and apoptosis is still under debate. The most obvious mechanism would be through the activation of TNF receptors by Fas (51), TRAIL (38,52), or TNF. Conversely, Panaretakis et al (17) suggested previously that interferon induces apoptosis through PI3K, which activates the downstream extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase C␦ (PKC␦), and JNK genes, leading to intrinsic apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Apelbaum

Yarden

Warszawski

et al. 2013

Molecular and Cellular Biology

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Interferons induce a pleiotropy of responses through binding the same cell surface receptor. Here we investigated the molecular mechanism driving interferon-induced apoptosis. Using a nonbiased small interfering RNA (siRNA) screen, we show that silencing genes whose products are directly engaged in the initiation of interferon signaling completely abrogate the interferon antiproliferative response. Apoptosis-related genes such as the caspase-8, cFLIP, and DR5 genes specifically interfere with interferon-induced apoptosis, which we found to be independent of the activity of death ligands. The one gene for which silencing resulted in the strongest proapoptotic effect upon interferon signaling is the cFLIP gene, where silencing shortened the time of initiation of apoptosis from days to hours and increased dramatically the population of apoptotic cells. Thus, cFLIP serves as a regulator for interferon-induced apoptosis. A shift over time in the balance between cFLIP and caspase-8 results in downstream caspase activation and apoptosis. While gamma interferon (IFN-␥) also causes caspase-8 upregulation, we suggest that it follows a different path to apoptosis.

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Section: Ifn-induced Apoptosis Is Death Ligand Independentmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Apelbaum

Yarden

Warszawski

et al. 2013

Molecular and Cellular Biology

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“…1E and 4D). This partial abrogation might be due to the insufficient ability of the Ab to neutralize the TRAIL activity, or alternatively, there could be TRAIL-independent mechanisms as recently reported in the mechanism for IFN-induced apoptosis [42]. DNase II-deficient embryos die in utero due to severe anemia caused by IFN-β produced in the macrophages carrying undigested DNA.…”

Section: Discussionmentioning

confidence: 92%

“…DNase II-deficient embryos die in utero due to severe anemia caused by IFN-β produced in the macrophages carrying undigested DNA. Although a high level of TRAIL mRNA was found in the fetal liver, a null mutation in TRAIL failed to rescue the lethal anemia, indicating that TRAIL is not necessary for inducing the apoptosis of erythroid cells in DNase II-deficient embryos [42]. Further studies are necessary to clarify the molecular mechanisms underlying IL-27 and poly(I:C)–mediated inhibition of tumor growth in TRAIL-dependent and -independent manners.…”

Section: Discussionmentioning

confidence: 99%

IL-27 Enhances the Expression of TRAIL and TLR3 in Human Melanomas and Inhibits Their Tumor Growth in Cooperation with a TLR3 Agonist Poly(I:C) Partly in a TRAIL-Dependent Manner

et al. 2013

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Interleukin (IL)-27 is a member of the IL-6/IL-12 cytokine family and possesses potent antitumor activity, which is mediated by multiple mechanisms. Toll-like receptor (TLR)3 is the critical sensor of the innate immune system that serves to identify viral double-stranded RNA. TLR3 is frequently expressed by various types of malignant cells, and recent studies reported that a synthetic TLR3 agonist, polyinosinic-polycytidylic acid [poly(I:C)], induces antitumor effects on malignant cells. In the present study, we have explored the effect of IL-27 on human melanomas and uncovered a previously unknown mechanism. We found that IL-27 inhibits in vitro tumor growth of human melanomas and greatly enhances the expression of TNF-related apoptosis inducing ligand (TRAIL) in a dose-dependent manner. Neutralizing antibody against TRAIL partly but significantly blocked the IL-27–mediated inhibition of tumor growth. In addition, IL-27 and poly(I:C) cooperatively augmented TRAIL expression and inhibited tumor growth. The cooperative effect could be ascribed to the augmented expression of TLR3, but not retinoic acid-inducible gene-I or anti-melanoma differentiation-associated gene 5, by IL-27. The inhibition of tumor growth by the combination was also significantly abrogated by anti-TRAIL neutralizing antibody. Moreover, IL-27 and poly(I:C) cooperatively suppressed in vivo tumor growth of human melanoma in immunodeficient mice. Taken together, these results suggest that IL-27 enhances the expression of TRAIL and TLR3 in human melanomas and inhibits their tumor growth in cooperation with poly(I:C), partly in a TRAIL-dependent manner. Thus, IL-27 and the combination of IL-27 and poly(I:C) may be attractive candidates for cancer immunotherapy.

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Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNβ‐1a Biologics

Hyland

Chekka

Samarth

et al. 2022

Clin Pharma and Therapeutics

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Proteomics has the potential to identify pharmacodynamic (PD) biomarkers for similarity assessment of proposed biosimilars without relying on clinical efficacy end points. In this study, with 36 healthy participants randomized to therapeutic doses of interferon-beta 1a products (IFNβ-1a) or pegylated-IFNβ-1a (pegIFNβ-1a) approved to treat multiple sclerosis or placebo, we evaluated the utility of a proteomic assay that profiles > 7,000 plasma proteins. IFNβ-1a and pegIFNβ-1a resulted in 248 and 528 differentially expressed protein analytes, respectively, between treatment and placebo groups over the time course. Thirty-one proteins were prioritized based on a maximal fold change ≥ 2 from baseline, baseline adjusted area under the effect curve (AUEC) and overlap between the 2 products. Of these, the majority had a significant AUEC compared with placebo in response to either product; 8 proteins showed > 4-fold maximal change from baseline. We identified previously reported candidates, beta-2microglobulin and interferon-induced GTP-binding protein (Mx1) with ~ 50% coefficient of variation (CV) for AUEC, and many new candidates (including I-TAC, C1QC, and IP-10) with CVs ranging from 26%-129%. Upstream regulator analysis of differentially expressed proteins predicted activation of IFNβ1 signaling as well as other cytokine, enzyme, and transcription signaling networks by both products. Although independent replication is required to confirm present results, our study demonstrates the utility of proteomics for the identification of individual and composite candidate PD biomarkers that may be leveraged to support clinical pharmacology studies for biosimilar approvals, especially when biologics have complex mechanisms of action or do not have previously characterized PD biomarkers.

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Interferon‐induced TRAIL‐independent cell death in DNase II^−/− embryos

Cited by 8 publications

References 40 publications

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

IL-27 Enhances the Expression of TRAIL and TLR3 in Human Melanomas and Inhibits Their Tumor Growth in Cooperation with a TLR3 Agonist Poly(I:C) Partly in a TRAIL-Dependent Manner

Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNβ‐1a Biologics

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Interferon‐induced TRAIL‐independent cell death in DNase II−/− embryos

Cited by 8 publications

References 40 publications

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

IL-27 Enhances the Expression of TRAIL and TLR3 in Human Melanomas and Inhibits Their Tumor Growth in Cooperation with a TLR3 Agonist Poly(I:C) Partly in a TRAIL-Dependent Manner

Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNβ‐1a Biologics

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Interferon‐induced TRAIL‐independent cell death in DNase II^−/− embryos