Positive feedback regulation of type I <i>IFN</i> genes by the IFN‐inducible transcription factor IRF‐7

Sato, Mitsuharu; Hata, Naoki; Asagiri, Masataka; Nakaya, Takeo; Taniguchi, Tadatsugu; Tanaka, Nobuyuki

doi:10.1016/s0014-5793(98)01514-2

Cited by 510 publications

(521 citation statements)

References 28 publications

(61 reference statements)

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“…4), while no such response is seen in IFNAR -/-cells. In fact, IRF7 expression is virtually extinguished in IFNAR -/-cells, consistent with known effects of constitutive type I IFN expression [35]. These data indicate that the primary mechanism of synergy does not require autocrine type I IFN signaling and up-regulation of IRF7.…”

supporting

confidence: 79%

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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supporting

confidence: 79%

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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“…IRF7 mRNA can be induced by type I IFN. The induction was suggested to be critical for IFN-␣ production through the analysis of IRF-9-deficient mice that lack IRF7 mRNA induction (27). However, wild-type DCs could produce similarly increased levels of IRF7 mRNA expression in response to 3 M ODN1668, although IFN-␣ production was profoundly decreased (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…IRF7 expression is induced by type I IFNs or viral infection and involved in type I IFN production (16,26,27). Therefore, we examined whether the IRF7 mRNA is differentially induced by the two types of CpG DNAs.…”

Section: Northern Blot Analysis Of Cpg Dna-stimulated Dcsmentioning

confidence: 99%

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The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets

Hemmi

Kaisho

Takeda

et al. 2003

The Journal of Immunology

303

208

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Oligodeoxynucleotides containing unmethylated CpG motifs (CpG DNAs) can function as powerful immune adjuvants by activating APC. Compared with conventional phosphorothioate-backbone CpG DNAs, another type of CpG DNAs, called an A or D type (A/D-type), possesses higher ability to induce IFN-α production. Conventional CpG DNAs can exert their activity through Toll-like receptor 9 (TLR9) signaling, which depends on a cytoplasmic adapter, MyD88. However, it remains unknown how A/D-type CpG DNAs exhibit their immunostimulatory function. In this study we have investigated murine dendritic cell (DC) responses to these two distinct CpG DNAs. Not only splenic, but also in vitro bone marrow-derived, DCs could produce larger amounts of IFN-α in response to A/D-type CpG DNAs compared with conventional CpG DNAs. This IFN-α production was mainly due to the B220+ DC subset. On the other hand, the B220− DC subset responded similarly to both CpG DNAs in terms of costimulatory molecule up-regulation and IL-12 induction. IFN-α, but not IL-12, induction was dependent on type I IFN. However, all activities of both CpG DNAs were abolished in TLR9- and MyD88-, but were retained in DNA-PKcs-deficient DCs. This study demonstrates that the TLR9-MyD88 signaling pathway is essential for all DC responses to both types of CpG DNAs.

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“…4A, lane 8), implying that a STAT1-containing complex is involved in the induction of IRF-7. Because the IRF-7 promoter contains an ISRE element, it seemed to be more likely that its transcription could be induced by the type I IFNs, IFN-a and IFN-h (30). We therefore wanted to investigate the possibility that BRCA1 and IFN-g may cooperate to induce this type I signaling pathway.…”

Section: Brca1 and Ifn-c Cooperate To Induce Components Of The Type Imentioning

confidence: 99%

BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs

Buckley

Hosey

Gorski

et al. 2007

Molecular Cancer Research

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BRCA1 encodes a tumor suppressor gene that is mutated in the germ line of women with a genetic predisposition to breast and ovarian cancer. BRCA1 has been implicated in a number of important cellular functions including DNA damage repair, transcriptional regulation, cell cycle control, and ubiquitination. Using an Affymetrix U95A microarray, IRF-7 was identified as a BRCA1 transcriptional target and was also shown to be synergistically up-regulated by BRCA1 specifically in the presence of IFN-;, coincident with the synergistic induction of apoptosis. We show that BRCA1, signal transducer and activator of transcription (STAT)-1, and STAT2 are all required for the induction of IRF-7 following stimulation with IFN-;. We also show that the induction of IRF-7 by BRCA1 and IFN-; is dependent on the type I IFNs, IFN-A and IFN-B. We show that BRCA1 is required for the up-regulation of STAT1, STAT2, and the type I IFNs in response to IFN-;. We show that BRCA1 is localized at the promoters of the molecules involved in type I IFN signaling leading to their up-regulation. Blocking this intermediary type I IFN step using specific antisera shows the requirement for IFN-A and IFN-B in the induction of IRF-7 and apoptosis. Finally, we outline a mechanism for the BRCA1/IFN-; regulation of target genes involved in the innate immune response, which is dependent on type I IFN signaling. (Mol Cancer Res 2007;5(3):261 -70)

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Positive feedback regulation of type I IFN genes by the IFN‐inducible transcription factor IRF‐7

Cited by 510 publications

References 28 publications

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

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

The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets

BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs

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