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Double-stranded RNA induces chicken T-cell lymphoma apoptosis by TRIF and NF-?B.

ABSTRACT: Toll-like receptor-3 (TLR3), a member of the pathogen recognition receptor family, has been reported to activate immune response and to exhibit pro-apoptotic activity against some tumor cells. However it is unclear whether TLR3 has same function against chicken lymphoma. In this paper we investigated the effect of TLR3 activation on a Marek's disease lymphoma-derived chicken cell line, MDCC-MSB1. The TLR3 agonist poly (I:C) activated TLR3 pathway and inhibited tumor cells proliferation through caspase-dependent apoptosis. Using pharmacological approaches, we found that an interferon-independent mechanism involving Toll-IL-1-receptor domain-containing adapter-inducing IFN-? (TRIF) and nuclear factor ?B (NF-?B) causes the apoptosis of MDCC-MSB1 cells. This is the first report about the function of TLR3 in chicken T-cell lymphoma, especially in signal pathway. The mechanisms underlying TLR3-mediated apoptosis may contribute to the development of new drug to treat lymphomas and oncovirus infections.

SUBMITTER: Zou H

PROVIDER: S-EPMC5548913 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Double-stranded RNA induces chicken T-cell lymphoma apoptosis by TRIF and NF-κB.

Zou Haitao H Su Ruixue R Ruan Jing J Shao Hongxia H Qian Kun K Ye Jianqiang J Yao Yongxiu Y Nair Venugopal V Qin Aijian A

Scientific reports 20170808 1

Toll-like receptor-3 (TLR3), a member of the pathogen recognition receptor family, has been reported to activate immune response and to exhibit pro-apoptotic activity against some tumor cells. However it is unclear whether TLR3 has same function against chicken lymphoma. In this paper we investigated the effect of TLR3 activation on a Marek's disease lymphoma-derived chicken cell line, MDCC-MSB1. The TLR3 agonist poly (I:C) activated TLR3 pathway and inhibited tumor cells proliferation through c ...[more]

PMID: 28790362

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Project description:BackgroundCytoplasmic viral double-stranded RNA (dsRNA) is detected by a class of ubiquitous cytoplasmic RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation antigen-5 (MDA5), which initiate a signaling cascade via their common adaptor called interferon-? (IFN-?) promoter stimulator-1 (IPS-1). This leads to the production of proinflammatory and antiviral cytokines, the type I Interferons, via mainly nuclear factor kappa B (NF-?B) and interferon response factor-3 (IRF3) transcription factors. Fas-associated death domain (FADD) protein, receptor-interacting protein (RIP1), caspase-8 and tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) protein, all traditionally associated with death receptor signaling, are also involved in RIG-I/MDA5 signaling pathway. We previously showed that FLIP (Flice-like inhibitory protein), also designated as cflar (CASP8 and FADD-like apoptosis regulator), negatively regulates lipopolysaccharide (LPS)-induced toll-like receptor 4 (TLR4) signaling in endothelial cells and mouse embryonic fibroblasts (MEFs) and protected against TLR4-mediated apoptosis.ResultsIn this study, we investigated the role of FLIP in cellular response to cytoplasmic polyinosinic:polycytidylic acid, poly(I:C), a synthetic analog of dsRNA. Consistent with the previously described role of FADD in RIG-I/MDA5-mediated apoptosis, we found that FLIP-/- MEFs were more susceptible to killing by cytoplasmic poly(I:C). However, FLIP-/- MEFs also exhibited markedly increased expression of NF-?B-and IRF3- dependent genes in response to cytoplasmic poly(I:C). Importantly, reconstitution of FLIP in FLIP-/-MEFs reversed the hyper-activation of IRF3- and NF-?B-mediated gene expression. Further, we found that caspase-8 catalytic activity was not required for cytoplasmic poly(I:C)-mediated NF-?B and IRF3 signaling.ConclusionsThese results provide evidence for a crucial dual role for FLIP in antiviral responses to cytoplasmic dsRNA: it protects from cytoplasmic dsRNA-mediated cell death while down-regulating IRF3-and NF-?B-mediated gene expression. Since the pathogenesis of several viral infections involves a heightened and dysregulated cytokine response, a possible therapy could involve modulating FLIP levels.

Dataset Information

Double-stranded RNA induces chicken T-cell lymphoma apoptosis by TRIF and NF-?B.

Publications

Double-stranded RNA induces chicken T-cell lymphoma apoptosis by TRIF and NF-κB.

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