Cross Talk Between Interferon-γ and -α/β Signaling Components in Caveolar Membrane Domains

Takaoka, Akinori; Mitani, Yukiko; Suemori, Hirofumi; Sato, Mitsuharu; Yokochi, Taeko; Noguchi, Shigeru; Tanaka, Nobuyuki; Taniguchi, Tadatsugu

doi:10.1126/science.288.5475.2357

Cited by 295 publications

(357 citation statements)

References 26 publications

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“…Furthermore, type I IFN promotes the production of IFN␥ and other cytokines such as IL-6, IL-10, and IL-15 that are important for sustained activation of the immune system (27). Type I IFN also potentiates the effects of IFN␥ and IL-6 (82,83) and shifts the actions of IL-10 from an antiinflammatory to a more proinflammatory profile (84). The increased expression of all of these molecules decreases the threshold for cellular activation and increases the likelihood for the initiation of an autoimmune reaction.…”

Section: Induction Of Autoimmunity By Type I Ifnmentioning

confidence: 99%

The type I interferon system in systemic lupus erythematosus

Rönnblom

Eloranta

Alm

2006

Arthritis & Rheumatism

301

246

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Section: Induction Of Autoimmunity By Type I Ifnmentioning

confidence: 99%

The type I interferon system in systemic lupus erythematosus

Rönnblom

Eloranta

Alm

2006

Arthritis & Rheumatism

301

246

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“…For example, weak IFN-b-mediated signaling augments IFN-a/b induction in response to LPS through positive feedback involving autocrine/ paracrine up-regulation of IFN regulatory factor (IRF)7. In addition, low levels of IFN-a/b prime cells to respond to IFN-c and IL-6 by providing a phosphorylated type I IFN receptor 'niche' for commonly used signaling molecules in proximity to other cytokine receptor complexes [3,4]. Mice deficient in IFN-b are more susceptible to viral infection, have lower numbers of macrophages and mature B cells, and exhibit reduced bone mass [5], as IFN-b is a positive regulator of bone formation through inhibition of osteoclast differentiation [6].…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

et al. 2008

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Type I IFN are strongly induced upon engagement of certain pattern recognition receptors by microbial products, and play key roles in regulating innate and adaptive immunity. It has become apparent that the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), in addition to restoring ER homeostasis, also influences the expression of certain inflammatory cytokines. However, the extent to which UPR signaling regulates type I IFN remains unclear. Here we show that cells undergoing a UPR respond to TLR4 and TLR3 ligands, and intracellular dsRNA, with log-fold greater IFN-b induction. This synergy is not dependent on autocrine type I IFN signaling, but unexpectedly requires the UPR transcription factor X-box binding protein 1 (XBP-1). Synergistic IFN-b induction also occurs in HLA-B27/human b 2 m-transgenic rat macrophages exhibiting a UPR as a consequence of HLA-B27 up-regulation, where it correlates with activation of XBP-1 splicing. Together these findings indicate that the cellular response to endogenous 'danger' that disrupts ER homeostasis is coupled to IFN-b induction by XBP-1, which has implications for the immune response and the pathogenesis of diseases involving the UPR.Key words: HLA-B27 Á Interferons Á Protein misfolding Á Unfolded protein response IntroductionInitially identified as antiviral cytokines, type I IFN (IFN-a/b) are now recognized to have diverse immunoregulatory effects activating macrophages and NK cells, promoting T cell survival and dendritic cell (DC) maturation, and increasing the production of Th1-polarizing cytokines to mediate innate and adaptive immune responses [1]. Type I IFN also exert biological effects at low and even constitutive levels of expression [2]. For example, weak IFN-b-mediated signaling augments IFN-a/b induction in response to LPS through positive feedback involving autocrine/ paracrine up-regulation of IFN regulatory factor (IRF)7. In addition, low levels of IFN-a/b prime cells to respond to IFN-c and IL-6 by providing a phosphorylated type I IFN receptor 'niche' for commonly used signaling molecules in proximity to other cytokine receptor complexes [3,4]. Mice deficient in IFN-b are more susceptible to viral infection, have lower numbers of macrophages and mature B cells, and exhibit reduced bone mass [5], as IFN-b is a positive regulator of bone formation through inhibition of osteoclast differentiation [6]. Thus, even constitutive levels of this cytokine are important in osteo-immune homeostasis.IFN-b is produced by most cell types upon viral infection, and in large amounts by macrophages and DC, following engagement of pattern recognition receptors (PRR) by conserved molecular structures referred to as pathogen-associated molecular patterns [7, 8]. PRR that mediate IFN-b induction include cell surface TLR4 and endosomal TLR3 for LPS and dsRNA, respectively [9]. In both instances increased IFN-b gene transcription occurs via TLR/IL-1R domain-containing adapter inducing IFN-b (TRIF)-dependent IRF3 and NF-jB activation. PRR in the retinoic ...

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“…IFNAR1 2/2 mice were purchased from B&K Universal Group Ltd. MEFs were prepared following a standard procedure 47 . The above mice were all on the C57BL/6 background.…”

Section: Mice Cell Cultures Viruses and Reagentsmentioning

confidence: 99%

“…The details of the retroviral expression vectors for the HPV16 E6 protein, E1A and wild-type p53 are mentioned in Supplementary Information. Retroviral transduction into MEFs was carried out as described previously 47,48 .…”

Section: Retroviral Expressionmentioning

confidence: 99%

“…RNA extraction and polymerase chain reaction with reverse transcription (RT-PCR) analysis were performed as described previously 47 . Quantitative real-time RT-PCR was performed with the Lightcycler and SYBR Green system (Roche Molecular Biochemicals), and the data were normalized by the expression level of 28S ribosomal RNA for each sample.…”

Section: Rna Analysismentioning

confidence: 99%

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Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence

Takaoka

Hayakawa

Yanai

et al. 2003

Nature

Self Cite

813

696

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Swift elimination of undesirable cells is an important feature in tumour suppression and immunity. The tumour suppressor p53 and interferon-a and -b (IFN-a/b) are essential for the induction of apoptosis in cancerous cells and in antiviral immune responses, respectively, but little is known about their interrelationship. Here we show that transcription of the p53 gene is induced by IFN-a/b, accompanied by an increase in p53 protein level. IFN-a/b signalling itself does not activate p53; rather, it contributes to boosting p53 responses to stress signals. We show examples in which p53 gene induction by IFN-a/b contributes to tumour suppression. Furthermore, we show that p53 is activated in virally infected cells to evoke an apoptotic response and that p53 is critical for antiviral defence of the host. Our study reveals a hitherto unrecognized link between p53 and IFN-a/b in tumour suppression and antiviral immunity, which may have therapeutic implications.The tumour suppressor p53, activated in response to DNA damage, induces cell cycle arrest or apoptosis through transcriptional activation of its target genes, hence having a central role in tumour suppression [1][2][3][4][5] . So far, it is not known whether p53 contributes to the immune responses that lead to the eradication of pathogens such as viruses. On the other hand, IFN-a/b, both of which are essential cytokines for antiviral immunity, are sometimes referred to as 'negative growth factors' , and manifest anti-oncogenic activities [6][7][8][9][10] . In fact, IFN-a/b are used for the treatment of some forms of human cancer but the molecular basis for the treatment is poorly understood [11][12][13] . Until know, little if anything has been known about the link between the p53 and IFN-a/b system. Induction of p53 protein by IFN-a/bWhen wild-type mouse embryonic fibroblasts (MEFs) were stimulated with IFN-b, a notable increase in the level of p53 was observed (Fig. 1a). A similar observation was made in cells stimulated with IFN-a (data not shown) but not with IFN-g ( Supplementary Fig. 1). The increase in p53 level with IFN-b treatment was dose-dependent, with about fourfold induction achieved at a high concentration of IFN-b (Fig. 1b). The p53 induction by IFN-b was also observed in two human hepatic cancer cell lines, HepG2 and HLE, p53 function being abrogated in the latter cells by a mutation in the DNA-binding domain 14 (Fig. 1c). We performed a pulse-chase experiment to examine whether the observed p53 protein induction is secondary to suppression of the p53 degradation pathway by IFN-b, typically the MDM2-mediated pathway [15][16][17] . However, no difference was observed in the half-life of p53 (40-45 min) between the IFN-treated and untreated MEFs (Fig. 1d), suggesting that p53 protein synthesis is induced by IFN-b stimulation. Induction of the p53 gene by IFN-a/bInformation is limited about the induction of the p53 gene 18 , and the above results prompted us to examine whether IFN-a/b induces p53 gene transcription. Inspection of mouse and human p53...

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Cross Talk Between Interferon-γ and -α/β Signaling Components in Caveolar Membrane Domains

Cited by 295 publications

References 26 publications

The type I interferon system in systemic lupus erythematosus

The type I interferon system in systemic lupus erythematosus

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence

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