Primary activation of interferon A and interferon B gene transcription by interferon regulatory factor 3

Juang, Yuang-T.; Lowther, William; Kellum, M.; Au, Wei-Chun; Lin, Rongtuan; Hiscott, John; Pitha, Paula M.

doi:10.1073/pnas.95.17.9837

Cited by 241 publications

(190 citation statements)

References 48 publications

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“…Recent studies from several groups have shown that IRF-3 is phosphorylated at the carboxyl-terminal serine cluster in infected cells and translocated to nucleus, whereby it interacts with the transcriptional coactivator, CBP/p300 (22)(23)(24). Overexpression of E1A that targets CBP/p300 inhibited IRF-3-mediated transactivation of IFNA promoter, thus providing additional evidence for the biological role of IRF-3-CBP/p300 interaction (25).…”

mentioning

confidence: 86%

Characterization of the Interferon Regulatory Factor-7 and Its Potential Role in the Transcription Activation of Interferon A Genes

Au¹,

Moore²,

LaFleur³

et al. 1998

Journal of Biological Chemistry

264

261

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mentioning

confidence: 86%

Characterization of the Interferon Regulatory Factor-7 and Its Potential Role in the Transcription Activation of Interferon A Genes

Au¹,

Moore²,

LaFleur³

et al. 1998

Journal of Biological Chemistry

264

261

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“…Inhibition of PI3K activity enhances poly(I:C)-and LPS-mediated NF-jB but not IRF3 activation in DC IFN-b gene expression requires cooperation between NF-jB [28,29] and IRF3 [30][31][32] transcription factors. Therefore, we quantified the levels of NF-jB and IRF3 DNA-binding activities in nuclear extracts from wortmannin-treated DC versus control counterparts following LPS or poly(I:C) stimulation.…”

Section: Pi3k Inhibition Enhances Ifn-b Synthesis In DC Stimulated Bymentioning

confidence: 97%

“…In line with data on IKKa/b phosphorylation and IjB-a protein degradation, wortmannin treatment increased levels of p65 and p50 translocating in the nucleus 1 h following exposure to poly(I:C) or LPS ( One important feature of the IFN-b gene is that its transcription enhancer consists of four important positive regulatory domains (PRD), PRDI-IV, required for its activation. While NF-jB members bind to PRDII element on human IFN-b promoter, IRF3 binds to adjacent PRDIII and PRDI elements (referred collectively as PRDIII-I) [30,33]. To analyze the direct influence of wortmannin on NF-jB and IRF-3-mediated transcriptional activities, we assessed reporter gene activities using promoters that contain either NF-jB-or IRF3-binding sites in HEK 293T cells stably expressing TLR3 or TLR4/MD2.…”

Section: Pi3k Inhibition Enhances Ifn-b Synthesis In DC Stimulated Bymentioning

confidence: 99%

Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-κB activation and IFN-β synthesis downstream of Toll-like receptor 3 and 4

Aksoy

Berghe²,

Detienne

et al. 2005

Eur. J. Immunol.

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Phosphoinositide 3-kinases (PI3K) are known to regulate Toll-like receptor (TLR)-mediated inflammatory responses, but their impact on the different pathways of TLR signaling remains to be clarified. Here, we investigated the consequences of pharmacological inhibition of PI3K on Toll-IL-1 receptor domain-containing adapterinducing IFN-b (TRIF)-dependent signaling, which induces IFN-b gene expression downstream of TLR3 and TLR4. First, treatment of monocyte-derived dendritic cells (DC) with wortmannin or LY294002 was found to enhance IFN-b expression upon TLR3 or TLR4 engagement. In the same models of DC activation, PI3K inhibition increased DNA-binding activity of NF-jB, but not interferon response factor (IRF)-3, the key transcription factors required for TLR-mediated IFN-b synthesis. In parallel, wortmannin-treated DC exhibited enhanced levels of IjB kinase (IKK)-a/b phosphorylation and IjB-a degradation with a concomitant increase in NF-jB nuclear translocation. Experiments carried out in HEK 293T cells stably expressing TLR3 or TLR4 confirmed that inhibition of PI3K activity enhances NF-jB-dependent promoters as well as IFN-b promoter activities without interfering with transcription at the positive regulatory domain III-I. Furthermore, wortmannin enhanced NF-jB activity induced by TRIF overexpression in HEK 293T cells, while overexpression of catalytically active PI3K selectively attenuated TRIF-mediated NF-jB transcriptional activity. Finally, in coimmunoprecipitation experiments, we showed that PI3K physically interacted with TRIF. We conclude that inhibition of PI3K activity enhances TRIF-dependent NF-jB activity, and thereby increases IFN-b synthesis elicited by TLR3 or TLR4 ligands.

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“…S3). We chose these cells because E1A antagonizes IRF3-dependent activation of IFN-I gene expression (35), thereby making it possible to control IFN stimulation by exogenous introduction of IFN. The expression of AdV Luc or AdV IKKε alone did not lead to the binding of ISGF3 or GAF to an ISRE or GAS element, respectively.…”

Section: Ifn-mentioning

confidence: 99%

IκB kinase ε (IKKε) regulates the balance between type I and type II interferon responses

Friedman

Schmid

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

109

103

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Virus infection induces the production of type I and type II interferons (IFN-I and IFN-II), cytokines that mediate the antiviral response. IFN-I (IFN-α and IFN-β) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9. IFN-II (IFN-γ) induces the homodimerization of STAT1 to form the gamma-activated factor (GAF) complex. ISGF3 and GAF bind specifically to unique regulatory DNA sequences located upstream of IFN-I-and IFN-II-inducible genes, respectively, and activate the expression of distinct sets of antiviral genes. The balance between type I and type II IFN pathways plays a critical role in orchestrating the innate and adaptive immune systems. Here, we show that the phosphorylation of STAT1 by IκB kinase epsilon (IKKε) inhibits STAT1 homodimerization, and thus assembly of GAF, but does not disrupt ISGF3 formation. Therefore, virus and/or IFN-I activation of IKKε suppresses GAF-dependent transcription and promotes ISGF3-dependent transcription. In the absence of IKKε, GAF-dependent transcription is enhanced at the expense of ISGF3-mediated transcription, rendering cells less resistant to infection. We conclude that IKKε plays a critical role in regulating the balance between the IFN-I and IFN-II signaling pathways.H ost immune defenses counteract virus infection by coordinating an intracellular innate immune response with the adaptive immune response. Systemically, the antiviral defense is generally cell-mediated, involving the recruitment and activation of dendritic cells, macrophages, neutrophils, and natural killer cells to the site of infection (1). This initial response is followed by a second wave of specific antiviral defenses involving cytotoxic T cells and antibodies generated from plasma B cells (2). The success of the adaptive immune response is intricately linked to the intracellular innate defenses initiated at the site of infection (1). The signaling required to coordinate the successful induction of the intracellular immune response to virus infection relies on the activation of interferon (IFN) genes, which encode cytokines with antiviral and immunomodulatory activity (3).The vertebrate type I IFN (IFN-I) genes are arranged in a large gene cluster consisting of a single IFNβ gene and several tandemly arranged IFNα genes encoding distinct isotypes (4, 5). In contrast to type I IFNs, type II IFN (IFN-II) is encoded by a single IFNγ gene. Although IFN-I mediates cellular resistance to virus infection, IFN-II confers limited cellular protection through the induction of a subset of genes that are shared between the IFN-I and IFN-II transcriptomes (6, 7). Virus infection leads to the activation of IFN-I genes and the secretion of IFNα and -β, which bind to IFN receptors at the cell surface. This, in turn, leads to the transcriptional activation of a group of IFN-stimulated genes (ISGs), and these ISGs collectively establish a nonpermissive environment for virus replication (6).The transcription...

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Primary activation of interferon A and interferon B gene transcription by interferon regulatory factor 3

Cited by 241 publications

References 48 publications

Characterization of the Interferon Regulatory Factor-7 and Its Potential Role in the Transcription Activation of Interferon A Genes

Characterization of the Interferon Regulatory Factor-7 and Its Potential Role in the Transcription Activation of Interferon A Genes

Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-κB activation and IFN-β synthesis downstream of Toll-like receptor 3 and 4

IκB kinase ε (IKKε) regulates the balance between type I and type II interferon responses

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