Constitutive IFN-α/β Signal for Efficient IFN-α/β Gene Induction by Virus

Hata, Naoki; Sato, Mitsuharu; Takaoka, Akinori; Asagiri, Masataka; Tanaka, Nobuyuki; Taniguchi, Tadatsugu

doi:10.1006/bbrc.2001.5159

Cited by 90 publications

(102 citation statements)

References 26 publications

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“…Also, it could be shown that defined DC cell populations react to different TLR stimuli and exhibit a specialized localization and migration pattern after in vivo stimulation with molecular pathogen compounds. Without stimulation, no YFP was detectable in vitro or in vivo, arguing against efficient protein production from any constitutive IFN␤ mRNA in untreated cells (18). The earliest time point YFP was detectable in vitro was Ϸ4 h after stimulation.…”

Section: Discussionmentioning

confidence: 96%

Visualization of IFNβ production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo

Scheu

Dresing

Locksley

2008

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

118

133

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Section: Discussionmentioning

confidence: 96%

Visualization of IFNβ production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo

Scheu

Dresing

Locksley

2008

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

118

133

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“…The regulation of constitutively induced type I IFN at the transcriptional level has mainly been studied in fibroblast cultures, in which it is clearly distinct from pathogen-induced IFN. While IRF3 and IRF7 are instrumental for PRR-triggered type I IFN production, they are dispensable for tonic type I IFN production [22,29]. On the other hand, AP-1 and NF-kB components are critically required for spontaneous type I IFN production, while being important, but not necessary, for pathogen-triggered IFN production [26,[29][30][31].…”

Section: Discussionmentioning

confidence: 99%

“…Even though it is difficult to conclude from early reports whether spontaneous I IFN production was actually studied under sterile conditions, several recent studies have unequivocally shown that certain cell types indeed produce low, but significant, levels of type I IFNs in the absence of infection. This phenomenon of tonic type I IFN production has been observed in mouse embryonic fibroblasts (MEFs) [22], myeloid dendritic cells [23,24], osteoclast precursors, and also in pDCs [25], where it is has been shown to modulate cell differentiation and immune responses. While the exact triggering mechanisms for spontaneous type I IFN production remain elusive for most cell types, it has been shown for osteoclast precursor cells that RANKL is responsible for the low, but constitute expression of IFN-β.…”

mentioning

confidence: 94%

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

et al. 2014

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Plasmacytoid dendritic cells (pDCs) are responsible for the robust and immediate production of type I IFNs during viral infection. pDCs employ TLR7 and TLR9 to detect RNA and CpG motifs present in microbial genomes. CpG-A was the first synthetic stimulus available that induced large amounts of IFN-α (type I IFN) in pDCs. CpG-B, however, only weakly activates pDCs to produce IFN-α. Here, we demonstrate that differences in the kinetics of TLR9 activation in human pDCs are essential for the understanding of the functional difference between CpG-A and CpG-B. While CpG-B quickly induces IFN-α production in pDCs, CpG-A stimulation results in delayed yet maximal IFN-α induction. Constitutive production of low levels of type I IFN in pDCs, acting in a paracrine and autocrine fashion, turned out to be the key mechanism responsible for this phenomenon. At high cell density, pDC-derived, constitutive type I IFN production primes pDCs for maximal TLR responsiveness. This accounts for the high activity of higher structured TLR agonists that trigger type I IFN production in a delayed fashion. Altogether, these data demonstrate that high type I IFN production by pDCs cannot be simply ascribed to cell-autonomous mechanisms, yet critically depends on the local immune context. Keywords:CpG-A r CpG-B r pDC r TLR9 r Type I IFN Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe recognition of invading pathogens and the initiation of an appropriate immune response are key functions of the innate immune system. TLRs are a family of PRRs that sense conserved microbial signatures, also known as PAMPs [1,2]. Among these, TLR9 detects unmethylated CpG-motifs, which are present in viral Correspondence: Prof. Veit Hornung e-mail: veit.hornung@uni-bonn.de and bacterial DNA, whereas TLR7 senses uridine-rich RNA. To prevent recognition of endogenous nucleic acids, both TLR7 and TLR9 are confined to endosomal compartments that are usually devoid of nucleic acids. While both TLR7 and TLR9 are broadly expressed in innate immune cells of the murine system, both TLR7 and TLR9 show a far more restricted expression pattern within the human system, with TLR9 expression restricted to B cells and pDCs. * These authors equally contributed to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 808Sarah Kim et al. Eur. J. Immunol. 2014. 44: 807-818 TLR9 traffics from the endoplasmic reticulum through the Golgi apparatus to acidic endosomal compartments, where it is proteolytically cleaved to achieve its signaling-competent state. Following ligand engagement, TLR9 initiates a signaling cascade, which is dependent on MyD88. In pDCs, MyD88 triggers a signaling complex consisting of IRAK1/4, TRAF3, and IKKα that leads to phosphorylation and nuclear translocation of interferon regulatory factor 7 (IRF7) and transcription of type I IFN genes. At the same time, TLR9 engagement activates NF-κB and subsequent proinflammatory gene expression [3]. For TLR9, di...

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“…Referring to IRFknockout studies in mouse cells, there is substantial evidence that different IRFs substitute each other in a redundant manner to ensure a robust host defense against viral infections. 38,47 Redundancy guarantees a kind of dynamic diversity whereby a specific function for a particular biological response can be replaced by different regulatory pathways. 36 It is therefore conceivable that various differentiation states are somehow ''frozen'' within a cell population, enabling descendant clones to stay alive under appropriate selection conditions.…”

Section: Discussionmentioning

confidence: 99%

Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

Bachmann

Zawatzky

Rösl

2007

Intl Journal of Cancer

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Although it is generally assumed that cancer arises from a singular cell, a tumor must be considered as a dynamic and emergent biological structure, whose organizing principle is determined by genetic and epigenetic modifications, occurring variably in response to microenvironmental selection conditions. As previously shown, HPV-positive cervical carcinoma cells have lost their ability to induce IFN-b upon TNF-a treatment. However, regarding cancer as a non-linear system, which may, even in the absence of an apparent selection pressure, fluctuate between different ''metastable'' phenotypes, we demonstrate that TNF-a mediated IFN-b induction is not irreversibly disturbed in all cells. Using the IFN-b sensitive Encephalomyocarditis virus (EMCV) as a tool to monitor antiviral activity in long-term established malignant HeLa cells, rare IFN-b expressing clones were rescued from a population of non-responsive and EMCV-sensitive cells. Antiviral activity was mediated by the re-expression of IRF-1 and p48 (IRF-9), both key regulatory molecules normally found to be suppressed in cervical carcinoma cells. Upon inoculating of selected clones into immunocompromised animals, a reduced or even an absence of tumorigenicity of initially highly malignant cells could be discerned. These data indicate that both the absence of interferon signaling and the ability to form tumors were reversed in a minority of cells. We provide a paradigm for the existence of innate genetic redundancy mechanisms, where a particular phenotype persists and can be isolated without application of drugs generally changing the epigenetic context. ' 2007 Wiley-Liss, Inc.Key words: human papillomaviruses; interferon-b regulation; EMCVcytolysis; tumor necrosis factor alpha; redundancy mechanisms; oscillation; chaotic cell systems; tumorigenicity Infections with certain types of human papillomaviruses (HPV) are the major cause for the development of cervical cancer. 1 Epidemiological studies show that immunodeficient women have a significantly higher risk of developing a tumor than age-matched controls. Hence, cancer of the cervix uteri is the final outcome of a long term selection and escape process, where HPV positive cells are no longer controlled by immunological surveillance. 2 Consequently, a physiological intact communication route between inflammatory and HPV-containing cells is an indispensable prerequisite for a proper antiviral response. 3 Targeting IFN-signaling actually provides a general selective advantage for tumor formation, because it favors the disruption of the intercellular cross-talk between HPV positive and immunological effector cells. 4 In a previous investigation, we demonstrated that the antiviral effect of TNF-a, which is mediated by IFN-b gene activation, 5 is disturbed in HPV positive cervical carcinoma cells. 6 The reason for this failure is the lack of interferon-regulatory factor (IRF)-1 and p48 (IRF-9) expression, two key regulators, tightly involved in the transcriptional control of the intermediate and the delayed interfero...

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Constitutive IFN-α/β Signal for Efficient IFN-α/β Gene Induction by Virus

Cited by 90 publications

References 26 publications

Visualization of IFNβ production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo

Visualization of IFNβ production by plasmacytoid versus conventional dendritic cells under specific stimulation conditions in vivo

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

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