Faculty Opinions recommendation of Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis.

AbstractAngiostrongylus cantonensis (AC) can cause severe eosinophilic meningitis or encephalitis in non-permissive hosts accompanied by apoptosis and necroptosis of brain cells. However, the explicit underlying molecular basis of apoptosis and necroptosis upon AC infection has not yet been elucidated. To determine the specific pathways of apoptosis and necroptosis upon AC infection, gene set enrichment analysis (GSEA) and protein–protein interaction (PPI) analysis for gene expression microarray (accession number: GSE159486) of mouse brain infected by AC revealed that TNF-α likely played a central role in the apoptosis and necroptosis in the context of AC infection, which was further confirmed via an in vivo rescue assay after treating with TNF-α inhibitor. The signalling axes involved in apoptosis and necroptosis were investigated via immunoprecipitation and immunoblotting. Immunofluorescence was used to identify the specific cells that underwent apoptosis or necroptosis. The results showed that TNF-α induced apoptosis of astrocytes through the RIP1/FADD/Caspase-8 axis and induced necroptosis of neurons by the RIP3/MLKL signalling pathway. In addition, in vitro assay revealed that TNF-α secretion by microglia increased upon LSA stimulation and caused necroptosis of neurons. The present study provided the first evidence that TNF-α was secreted by microglia stimulated by AC infection, which caused cell death via parallel pathways of astrocyte apoptosis (mediated by the RIP1/FADD/caspase-8 axis) and neuron necroptosis (driven by the RIP3/MLKL complex). Our research comprehensively elucidated the mechanism of cell death after AC infection and provided new insight into targeting TNF-α signalling as a therapeutic strategy for CNS injury.

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TNF-α-induced impairment of mitochondrial integrity and apoptosis mediated by caspase-8 in adult ventricular myocytes

Cytokine ◽

10.1016/j.cyto.2006.04.010 ◽

2006 ◽

Vol 34 (1-2) ◽

pp. 96-105 ◽

Cited By ~ 43

Author(s):

JiaXuan Zhu ◽

MeeiYueh Liu ◽

Richard H. Kennedy ◽

Shi J. Liu

Keyword(s):

Ventricular Myocytes ◽

Caspase 8 ◽

Mitochondrial Integrity ◽

Tnf Α

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Pharmacological Inhibition of Caspase-8 Suppresses Inflammation-Induced Angiogenesis in the Cornea

Biomolecules ◽

10.3390/biom10020210 ◽

2020 ◽

Vol 10 (2) ◽

pp. 210

Author(s):

Yunzhe Tian ◽

He Li ◽

Xiuxing Liu ◽

Lihui Xie ◽

Zhaohao Huang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Therapeutic Potential ◽

Corneal Neovascularization ◽

Caspase 8 ◽

Inhibitory Effects ◽

Toll Like Receptor 4 ◽

Pharmacological Inhibition ◽

Cytokines And Chemokines ◽

Tnf Α

Inflammation-induced angiogenesis is closely related to many diseases and has been regarded as a therapeutic target. Caspase-8 has attracted increasing attention for its immune properties and therapeutic potential in inflammatory disorders. The aim of our study is to investigate the clinical application of pharmacological inhibition of caspase-8 and the underlying molecular mechanisms in inflammation-induced angiogenesis in the cornea. A model of alkali burn (AB)-induced corneal neovascularization (CNV) in C57BL/6 wild-type (WT) mice and toll-like receptor 4 knockout (Tlr4-/-) mice was used. We found that AB increased caspase-8 activity and the pharmacological inhibition of caspase-8 exerted substantial inhibitory effects on CNV, with consistent decreases in caspase-8 activity, inflammatory cell infiltration, macrophage recruitment and activation, VEGF-A, TNF-α, IL-1β, MIP-1, and MCP-1 expression in the cornea. In vitro, caspase-8 mediated TLR4–dependent chemokines and VEGF-A production by macrophages. The TLR4 knockout significantly alleviated CNV, suppressed caspase-8 activity and downregulated expression of inflammatory cytokines and chemokines after AB. Taken together, these findings provide the first demonstration that the pharmacological inhibition of caspase-8 suppresses inflammation-induced angiogenesis and support the use of a pharmacological caspase-8 inhibitor as a novel clinical treatment for CNV and other angiogenic disorders.

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JAG2/Notch2 inhibits intervertebral disc degeneration by modulating cell proliferation, apoptosis, and extracellular matrix

Arthritis Research & Therapy ◽

10.1186/s13075-019-1990-z ◽

2019 ◽

Vol 21 (1) ◽

Cited By ~ 3

Author(s):

Jun Long ◽

Xiaobo Wang ◽

Xianfa Du ◽

Hehai Pan ◽

Jianru Wang ◽

...

Keyword(s):

Cell Cycle ◽

Extracellular Matrix ◽

Cell Proliferation ◽

Intervertebral Disc ◽

Notch Signaling ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Caspase 8 ◽

Tnf Α ◽

Intradiscal Injection

Abstract Background Intervertebral disc degeneration (IVDD)-related disorders are the major causes of low back pain. A previous study suggested that Notch activation serves as a protective mechanism and is a part of the compensatory response that maintains the necessary resident nucleus pulposus (NP) cell proliferation to replace lost or non-functional cells. However, the exact mechanism remains to be determined. In this study, we aimed to investigate the role of JAG2/Notch2 in NP cell proliferation and apoptosis. Methods Recombinant JAG2 or Notch2, Hes1, and Hey2 siRNAs were used to activate or inhibit Notch signaling. Cell proliferation, apoptosis, cell cycle regulatory factors, and pathways associated with Notch-mediated proliferation were examined. In vivo experiments involving an intradiscal injection of Sprague-Dawley rats were performed. Results Recombinant JAG2 induced Notch2 and Hes1/Hey2 expression together with NP cell proliferation. Downregulation of Notch2/Hes1/Hey2 induced G0/G1 phase cell cycle arrest in NP cells. Moreover, Notch2 mediated NP cell proliferation by regulating cyclin D1 and by activating PI3K/Akt and Wnt/β-catenin signaling. Furthermore, Notch signaling inhibited TNF-α-promoted NP cell apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Finally, we found that intradiscal injection of JAG2 alleviated IVDD and that sh-Notch2 aggravated IVDD in a rat model. These results indicated that JAG2/Notch2 inhibited IVDD by modulating cell proliferation, apoptosis, and extracellular matrix. The JAG2/Notch2 axis regulated NP cell proliferation via PI3K/Akt and Wnt/β-catenin signaling and inhibited TNF-α-induced apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Conclusions The current and previous results shed light on the therapeutic implications of targeting the JAG2/Notch2 axis to inhibit or reverse IVDD.

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Heat shock and tumor necrosis factor-α induce apoptosis in bovine preimplantation embryos through a caspase-9-dependent mechanism

Reproduction ◽

10.1530/rep-06-0307 ◽

2007 ◽

Vol 133 (6) ◽

pp. 1129-1137 ◽

Cited By ~ 20

Author(s):

Bárbara Loureiro ◽

Amber Mary Brad ◽

Peter James Hansen

Keyword(s):

Heat Shock ◽

Tumor Necrosis ◽

Preimplantation Embryos ◽

Caspase 8 ◽

Mitochondrial Depolarization ◽

Caspase 9 ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor ◽

Dependent Mechanism

Heat shock and tumor necrosis factor-α (TNF-α) induce apoptosis through different mechanisms, with heat shock acting to cause mitochondrial depolarization and caspase-9 activation, while TNF-α acts through a receptor-mediated process to activate caspase-8. In some cells, however, TNF-α can also cause mitochondrial depolarization and caspase-9 activation. In the present study, we tested the hypothesis that heat shock at 41 °C and TNF-α induce apoptosis in bovine preimplantation embryos through a caspase-9-dependent mechanism. Treatment of embryos with either heat shock (41 °C) or TNF-α increased the proportion of blastomeres that were TUNEL positive and the proportion of embryos exhibiting elevated caspase-9 activity. Furthermore, the caspase-9 inhibitor, z-LEHD-fmk, blocked the increase in TUNEL-positive nuclei caused by both heat shock and TNF-α. For embryos at day 6 after insemination, for example, the percent of blastomeres positive for TUNEL was 3.6% for control embryos, 11.1% for embryos cultured at 41 °C, and 15.1% for embryos cultured with 10 ng/ml TNF-α. In the presence of z-LEHD-fmk, the percent of cells positive for TUNEL was 3.7% for control embryos, 6.1% for embryos cultured at 41 °C, and 8% for embryos cultured with 10 ng/ml TNF-α. Although TNF-α did not cause a measurable increase in caspase-8 activity, there was a tendency (P= 0.07) for treatment of embryos with z-IETD-fmk, an inhibitor of caspase-8, to partly reduce the magnitude of the increase in TUNEL-positive cells caused by TNF-α. The percent of cells that were TUNEL positive was increased by TNF-α from 9.7 to 19.7% in the absence of inhibitor and from 13.0 to 15.6% in the presence of z-IETD-fmk. Results indicate that induction of apoptosis by both heat shock and TNF-α involve activation of caspase-9-dependent pathways. It is likely that TNF-α also activates apoptotic pathways involving caspase-8 but that the degree of activation is small and caspase-9-dependent pathways are required for full activation of apoptosis.

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Carbon monoxide protects hepatocytes from TNF-α/Actinomycin D by inhibition of the caspase-8-mediated apoptotic pathway

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2006.03.180 ◽

2006 ◽

Vol 344 (4) ◽

pp. 1172-1178 ◽

Cited By ~ 23

Author(s):

Hoe Suk Kim ◽

Patricia A. Loughran ◽

Peter K. Kim ◽

Timothy R. Billiar ◽

Brian S. Zuckerbraun

Keyword(s):

Carbon Monoxide ◽

Actinomycin D ◽

Caspase 8 ◽

Apoptotic Pathway ◽

Tnf Α

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Caspase-8 controls the secretion of inflammatory lysyl-tRNA synthetase in exosomes from cancer cells

The Journal of Cell Biology ◽

10.1083/jcb.201605118 ◽

2017 ◽

Vol 216 (7) ◽

pp. 2201-2216 ◽

Cited By ~ 38

Author(s):

Sang Bum Kim ◽

Hye Rim Kim ◽

Min Chul Park ◽

Seongmin Cho ◽

Peter C. Goughnour ◽

...

Keyword(s):

Cancer Cells ◽

Trna Synthetase ◽

Carcinoma Cells ◽

Caspase 8 ◽

Binding Motif ◽

Trna Synthetases ◽

C Terminus ◽

Tnf Α ◽

Unconventional Secretion ◽

Control Protein

Aminoacyl-tRNA synthetases (ARSs), enzymes that normally control protein synthesis, can be secreted and have different activities in the extracellular space, but the mechanism of their secretion is not understood. This study describes the secretion route of the ARS lysyl-tRNA synthetase (KRS) and how this process is regulated by caspase activity, which has been implicated in the unconventional secretion of other proteins. We show that KRS is secreted from colorectal carcinoma cells within the lumen of exosomes that can trigger an inflammatory response. Caspase-8 cleaved the N-terminal of KRS, thus exposing a PDZ-binding motif located in the C terminus of KRS. Syntenin bound to the exposed PDZ-binding motif of KRS and facilitated the exosomic secretion of KRS dissociated from the multi-tRNA synthetase complex. KRS-containing exosomes released by cancer cells induced macrophage migration, and their secretion of TNF-α and cleaved KRS made a significant contribution to these activities, which suggests a novel mechanism by which caspase-8 may promote inflammation.

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