Intracellular interferon triggers Jak/Stat signaling cascade and induces p53-dependent antiviral protection

Shin‐Ya, Masaharu; Hirai, Hideyo; Satoh, Etsuko; Kishida, Tsunao; Asada, Hidetsugu; Aoki, Fumiko; Tsukamoto, Masako; Imanishi, Jirô; Mazda, Osam

doi:10.1016/j.bbrc.2005.02.088

Cited by 21 publications

(21 citation statements)

References 29 publications

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“…Our data is in direct contrast to previous reports that p53 enhances type I IFN signaling pathway in normal cells and some cancer cell lines (Dharel et al, 2008; Lazo and Santos, 2011; Munoz-Fontela et al, 2005; Munoz-Fontela et al, 2011; Munoz-Fontela et al, 2008; Shin-Ya et al, 2005; Su et al, 2009; Takaoka et al, 2003; Yonish-Rouach et al, 1991). There are several potential reasons for the discrepancy between our results in human PDAC cells and previous results in other cell types: 1) differences between normal and cancer cells (and between different cancer cell types) in antiviral signaling, 2) constitutive activation of NF-κB pathway in a majority of PDACs, and 3) different timing and level of expression for VSV-encoded p53 in our study, and constitutively expressed p53 transgenes in other studies.…”

Section: Discussioncontrasting

confidence: 99%

“…Several studies showed that in normal cells and some cancer cell lines, p53 inhibited virus replication via enhanced type I Interferon (IFN) antiviral signaling (Dharel et al, 2008; Lazo and Santos, 2011; Munoz-Fontela et al, 2005; Munoz-Fontela et al, 2011; Munoz-Fontela et al, 2008; Shin-Ya et al, 2005; Su et al, 2009; Takaoka et al, 2003; Yonish-Rouach et al, 1991). In agreement with this, many viruses directly target and inhibit p53 activities in infected cells [reviewed in (Sato and Tsurumi, 2013)].…”

Section: Introductionmentioning

confidence: 99%

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An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

et al. 2015

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Virus-encoded tumor suppressor p53 transgene expression has been successfully used in vesicular stomatitis virus (VSV) and other oncolytic viruses (OVs) to enhance their anticancer activities. However, p53 is also known to inhibit virus replication via enhanced type I interferon (IFN) antiviral responses. To examine whether p53 transgenes enhance antiviral signaling in human pancreatic ductal adenocarcinoma (PDAC) cells, we engineered novel VSV recombinants encoding human p53 or the previously described chimeric p53-CC, which contains the coiled-coil (CC) domain from breakpoint cluster region (BCR) protein and evades the dominant-negative activities of endogenously expressed mutant p53. Contrary to an expected enhancement of antiviral signaling by p53, our global analysis of gene expression in PDAC cells showed that both p53 and p53-CC dramatically inhibited type I IFN responses. Our data suggest that this occurs through p53-mediated inhibition of the NF-κB pathway. Importantly, VSV-encoded p53 or p53-CC did not inhibit antiviral signaling in non-malignant human pancreatic ductal cells, which retain their resistance to all VSV recombinants. To the best of our knowledge, this is the first report of p53-mediated inhibition of antiviral signaling, and it suggests that OV-encoded p53 can simultaneously produce anticancer activities while assisting, rather than inhibiting, virus replication in cancer cells.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

et al. 2015

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“…In line with these findings on the role of TYK2 in MHC class I regulation, granulocytemacrophage colony-stimulating factor-induced downregulation of TYK2 and JAK1 tyrosine phosphorylation, as well as TYK2 protein expression, contributes to decreased STAT1 phosphorylation and subsequently diminished MHC class I antigen levels in hematopoietic cell lines (43). Furthermore, IFNb-stimulated MHC class I expression is abrogated when JAK1, TYK2, or the IFNa/b receptor is suppressed by siRNAs in human Ewing sarcoma cell line (44).…”

Section: Discussionsupporting

confidence: 69%

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

et al. 2015

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Pancreatic b-cells are destroyed by an autoimmune attack in type 1 diabetes. Linkage and genome-wide association studies point to >50 loci that are associated with the disease in the human genome. Pathway analysis of candidate genes expressed in human islets identified a central role for interferon (IFN)-regulated pathways and tyrosine kinase 2 (TYK2). Polymorphisms in the TYK2 gene predicted to decrease function are associated with a decreased risk of developing type 1 diabetes. We presently evaluated whether TYK2 plays a role in human pancreatic b-cell apoptosis and production of proinflammatory mediators. TYK2-silenced human b-cells exposed to polyinosinicpolycitidilic acid (PIC) (a mimick of double-stranded RNA produced during viral infection) showed less type I IFN pathway activation and lower production of IFNa and CXCL10. These cells also had decreased expression of major histocompatibility complex (MHC) class I proteins, a hallmark of early b-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PICinduced b-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways in pancreatic b-cells via modulation of IFNa signaling, subsequent increase in MHC class I protein, and modulation of chemokines such as CXCL10 that are important for recruitment of T cells to the islets.

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“…It should be noted that complete inhibition of IFN-β production was not obtained by addition of an IFNαβR mAb. This may be due to the presence of intracellular type I IFNR (28). Taken together, these data provide strong evidence that NOD1 induction of IFN-β synthesis does in fact result in the production of IP-10.…”

Section: Figurementioning

confidence: 52%

NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway

Watanabe¹,

Asano²,

et al. 2010

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Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular epithelial cell protein known to play a role in host defense at mucosal surfaces. Here we show that a ligand specific for NOD1, a peptide derived from peptidoglycan, initiates an unexpected signaling pathway in human epithelial cell lines that results in the production of type I IFN. Detailed analysis revealed the components of the signaling pathway. NOD1 binding to its ligand triggered activation of the serine-threonine kinase RICK, which was then able to bind TNF receptor-associated factor 3 (TRAF3). This in turn led to activation of TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) and the subsequent activation of IFN regulatory factor 7 (IRF7). IRF7 induced IFN-β production, which led to activation of a heterotrimeric transcription factor complex known as IFN-stimulated gene factor 3 (ISGF3) and the subsequent production of CXCL10 and additional type I IFN. In vivo studies showed that mice lacking the receptor for IFN-β or subjected to gene silencing of the ISGF3 component Stat1 exhibited decreased CXCL10 responses and increased susceptibility to Helicobacter pylori infection, phenotypes observed in NOD1-deficient mice. These studies thus establish that NOD1 can activate the ISGF3 signaling pathway that is usually associated with protection against viral infection to provide mice with robust type I IFN-mediated protection from H. pylori and possibly other mucosal infections.

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Intracellular interferon triggers Jak/Stat signaling cascade and induces p53-dependent antiviral protection

Cited by 21 publications

References 29 publications

An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway

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