Activation of the Transcription Factor ISGF3 by Interferon-gamma

1999 ◽  
Vol 380 (6) ◽  
pp. 699-703 ◽  
Author(s):  
M. Matsumoto ◽  
N. Tanaka ◽  
H. Harada ◽  
T. Kimura ◽  
T. Yokochi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Type I ◽  
Type Ii ◽  
Additional Mechanism ◽  
Embryonic Fibroblasts ◽  
Signal Transducers ◽  
Stat Proteins ◽  
Antiviral Activities ◽  
Ifn Γ ◽  
Binding Component

AbstractThe interferon-stimulated gene factor 3 (ISGF3) transcription factor has been extensively studied in the context of the type I interferon (IFN-α/β)-mediated antiviral response; it consists of the major DNA-binding component p48, and the signal transducers and activators of transcription (Stat)1 and Stat2. We show here that type II IFN (IFN-γ) can also invoke the activation of ISGF3 in mouse primary embryonic fibroblasts. In fact, the two Stat proteins were tyrosine phosphorylated in IFN-γ stimulated cells. Our present findings reveal an additional mechanism by which these two distinct types of cytokines, IFN-α/β and -γ, can commonly elicit antiviral activities.

scholarly journals Respiratory Failure Due to Differentiation Arrest and Expansion of Alveolar Cells following Lung-Specific Loss of the Transcription Factor C/EBPα in Mice

2006 ◽  
Vol 26 (3) ◽  
pp. 1109-1123 ◽  
Author(s):  
Daniela S. Bassères ◽  
Elena Levantini ◽  
Hongbin Ji ◽  
Stefano Monti ◽  
Shannon Elf ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Respiratory Failure ◽  
Leucine Zipper ◽  
Type I ◽  
Type Ii ◽  
Alveolar Cells ◽  
Proliferating Cells ◽  
Therapeutic Benefits ◽  
Factor C

ABSTRACT The leucine zipper family transcription factor CCAAT enhancer binding protein alpha (C/EBPα) inhibits proliferation and promotes differentiation in various cell types. In this study, we show, using a lung-specific conditional mouse model of C/EBPα deletion, that loss of C/EBPα in the respiratory epithelium leads to respiratory failure at birth due to an arrest in the type II alveolar cell differentiation program. This differentiation arrest results in the lack of type I alveolar cells and differentiated surfactant-secreting type II alveolar cells. In addition to showing a block in type II cell differentiation, the neonatal lungs display increased numbers of proliferating cells and decreased numbers of apoptotic cells, leading to epithelial expansion and loss of airspace. Consistent with the phenotype observed, genes associated with alveolar maturation, survival, and proliferation were differentially expressed. Taken together, these results identify C/EBPα as a master regulator of airway epithelial maturation and suggest that the loss of C/EBPα could also be an important event in the multistep process of lung tumorigenesis. Furthermore, this study indicates that exploring the C/EBPα pathway might have therapeutic benefits for patients with respiratory distress syndromes.

scholarly journals Potent Inhibition of SARS-Associated Coronavirus (SCoV) Infection and Replication by Type I Interferons (IFN-α/β) but Not by Type II Interferon (IFN-γ)

2004 ◽  
Vol 24 (7) ◽  
pp. 388-390 ◽  
Author(s):  
Bojian Zheng ◽  
Ming-Liang He ◽  
King-Ling Wong ◽  
Ching Tung Lum ◽  
Leo L.M. Poon ◽  
...  
Keyword(s):  
Type I Interferons ◽  
Type I ◽  
Type Ii ◽  
Potent Inhibition ◽  
Ifn Γ

Congenital diaphragmatic hernia, tracheal occlusion, thyroid transcription factor-1, and fetal pulmonary epithelial maturation

2005 ◽  
Vol 289 (1) ◽  
pp. L44-L52 ◽  
Author(s):  
Cheryl J. Chapin ◽  
Robert Ertsey ◽  
Jyoji Yoshizawa ◽  
Akihiko Hara ◽  
Lourenco Sbragia ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dna Content ◽  
Pulmonary Hypoplasia ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii ◽  
Lung Growth ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Transcription Factor 1

Congenital diaphragmatic hernia (CDH) occurs in ∼1:2,500 human births and has high morbidity and mortality rates, primarily due to pulmonary hypoplasia and pulmonary hypertension. Tracheal occlusion (TO), in experimental animals, distends lungs and increases lung growth and alveolar type I cell maturation but decreases surfactant components and reduces alveolar type II cell density. We examined effects of CDH and CDH+TO on lung growth and maturation in fetal rats. To induce CDH, we administered nitrofen (100 mg) to dams at 9.5 days of gestation. We compared lungs from fetuses with CDH, CDH+TO, and those exposed to nitrofen without CDH. CDH decreased lung wet weight bilaterally ( P < 0.0001) and DNA content in lung ipsilateral to CDH ( P < 0.05). CDH+TO significantly increased lung wet weights bilaterally; DNA content was intermediate between CDH and NC. To evaluate effects on the distal pulmonary epithelium, we examined surfactant mRNA and protein levels, type I and II cell-specific markers (RTI40 and RTII70, respectively), and transcriptional regulator thyroid transcription factor-1 (TTF-1). Decreased lung distension (due to CDH) increased SP-C mRNA and TTF-1 protein expression and reduced RTI40 ( P < 0.05 for all). Increased lung distension (due to CDH+TO) reduced expression of SP mRNAs and pro-SP-C and TTF-1 proteins and enhanced expression of RTI40 (mRNA and protein; P < 0.05 for all). We conclude that CDH+TO partially reverses effects of CDH; it corrects the pulmonary hypoplasia and restores type I cell differentiation but adversely affects SP expression in type II cells. These effects may be mediated through changes in TTF-1 expression.

scholarly journals Casein Kinase 1α Mediates the Degradation of Receptors for Type I and Type II Interferons Caused by Hemagglutinin of Influenza A Virus

2018 ◽  
Vol 92 (7) ◽  
Author(s):  
Chuan Xia ◽  
Jennifer J. Wolf ◽  
Madhuvanthi Vijayan ◽  
Caleb J. Studstill ◽  
Wenjun Ma ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
P38 Map Kinase ◽  
Casein Kinase ◽  
Type I ◽  
Type Ii ◽  
Ifn Γ ◽  
Cellular Responsiveness ◽  
Novel Strategy

ABSTRACTAlthough influenza A virus (IAV) evades cellular defense systems to effectively propagate in the host, the viral immune-evasive mechanisms are incompletely understood. Our recent data showed that hemagglutinin (HA) of IAV induces degradation of type I IFN receptor 1 (IFNAR1). Here, we demonstrate that IAV HA induces degradation of type II IFN (IFN-γ) receptor 1 (IFNGR1), as well as IFNAR1, via casein kinase 1α (CK1α), resulting in the impairment of cellular responsiveness to both type I and II IFNs. IAV infection or transient HA expression induced degradation of both IFNGR1 and IFNAR1, whereas HA gene-deficient IAV failed to downregulate the receptors. IAV HA caused the phosphorylation and ubiquitination of IFNGR1, leading to the lysosome-dependent degradation of IFNGR1. Influenza viral HA strongly decreased cellular sensitivity to type II IFNs, as it suppressed the activation of STAT1 and the induction of IFN-γ-stimulated genes in response to exogenously supplied recombinant IFN-γ. Importantly, CK1α, but not p38 MAP kinase or protein kinase D2, was proven to be critical for HA-induced degradation of both IFNGR1 and IFNAR1. Pharmacologic inhibition of CK1α or small interfering RNA (siRNA)-based knockdown of CK1α repressed the degradation processes of both IFNGR1 and IFNAR1 triggered by IAV infection. Further, CK1α was shown to be pivotal for proficient replication of IAV. Collectively, the results suggest that IAV HA induces degradation of IFN receptors via CK1α, creating conditions favorable for viral propagation. Therefore, the study uncovers a new immune-evasive pathway of influenza virus.IMPORTANCEInfluenza A virus (IAV) remains a grave threat to humans, causing seasonal and pandemic influenza. Upon infection, innate and adaptive immunity, such as the interferon (IFN) response, is induced to protect hosts against IAV infection. However, IAV seems to be equipped with tactics to evade the IFN-mediated antiviral responses, although the detailed mechanisms need to be elucidated. In the present study, we show that IAV HA induces the degradation of the type II IFN receptor IFNGR1 and thereby substantially attenuates cellular responses to IFN-γ. Of note, a cellular kinase, casein kinase 1α (CK1α), is crucial for IAV HA-induced degradation of both IFNGR1 and IFNAR1. Accordingly, CK1α is proven to positively regulate IAV propagation. Thus, this study unveils a novel strategy employed by IAV to evade IFN-mediated antiviral activities. These findings may provide new insights into the interplay between IAV and host immunity to impact influenza virus pathogenicity.

scholarly journals Stat-mediated Signaling Induced by Type I and Type II Interferons (IFNs) Is Differentially Controlled through Lipid Microdomain Association and Clathrin-dependent Endocytosis of IFN Receptors

2006 ◽  
Vol 17 (7) ◽  
pp. 2896-2909 ◽  
Author(s):  
Marta Marchetti ◽  
Marie-Noelle Monier ◽  
Alexandre Fradagrada ◽  
Keith Mitchell ◽  
Florence Baychelier ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Biological Activities ◽  
Critical Role ◽  
Membrane Lipid ◽  
Endocytic Pathway ◽  
Type I ◽  
Type Ii ◽  
Biological Responses ◽  
Signal Specificity ◽  
Ifn Γ

Type I (α/β) and type II (γ) interferons (IFNs) bind to distinct receptors, although they activate the same signal transducer and activator of transcription, Stat1, raising the question of how signal specificity is maintained. Here, we have characterized the sorting of IFN receptors (IFN-Rs) at the plasma membrane and the role it plays in IFN-dependent signaling and biological activities. We show that both IFN-α and IFN-γ receptors are internalized by a classical clathrin- and dynamin-dependent endocytic pathway. Although inhibition of clathrin-dependent endocytosis blocked the uptake of IFN-α and IFN-γ receptors, this inhibition only affected IFN-α–induced Stat1 and Stat2 signaling. Furthermore, the antiviral and antiproliferative activities induced by IFN-α but not IFN-γ were also affected. Finally, we show that, unlike IFN-α receptors, activated IFN-γ receptors rapidly become enriched in plasma membrane lipid microdomains. We conclude that IFN-R compartmentalization at the plasma membrane, through clathrin-dependent endocytosis and lipid-based microdomains, plays a critical role in the signaling and biological responses induced by IFNs and contributes to establishing specificity within the Jak/Stat signaling pathway.

Acute Liver Failure Following Minocycline Treatment – A Case Report and Review of the Literature

2012 ◽  
Vol 50 (08) ◽  
pp. 771-775 ◽  
Author(s):  
A. Kuhn ◽  
C. Weiler-Normann ◽  
C. Schramm ◽  
S. Kluge ◽  
M. Behne ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Experimental Studies ◽  
Type I ◽  
Type Ii ◽  
Minocycline Treatment ◽  
Tnf Α ◽  
Ige Mediated ◽  
Ifn Γ

AbstractWe present the case of a 23-year-old female patient with acute liver failure following intake of minocycline. This patient had severe hypereosinophilia and massively increased IgE levels. Experimental studies in this case revealed elevated IFN-γ-, as well as TNF-α-producing CD4+ and CD8+ T-cells after in vitro stimulation with minocycline, indicating a type I/IgE-mediated as well as type II/cytotoxic reaction in the pathogenesis of minocycline-induced liver failure. Although mild forms of liver involvement are well known side effects of minocycline, only 8 cases with acute liver failure have been reported, and we present a review of all cases.

scholarly journals Interferon Regulatory Factor 1 Protects against Chikungunya Virus-Induced Immunopathology by Restricting Infection in Muscle Cells

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Sharmila Nair ◽  
Subhajit Poddar ◽  
Raeann M. Shimak ◽  
Michael S. Diamond
Keyword(s):  
Chikungunya Virus ◽  
Muscle Cells ◽  
Interferon Regulatory Factor ◽  
Ross River Virus ◽  
Type I ◽  
Type Ii ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
Ifn Γ

ABSTRACT The innate immune system protects cells against viral pathogens in part through the autocrine and paracrine actions of alpha/beta interferon (IFN-α/β) (type I), IFN-γ (type II), and IFN-λ (type III). The transcription factor interferon regulatory factor 1 (IRF-1) has a demonstrated role in shaping innate and adaptive antiviral immunity by inducing the expression of IFN-stimulated genes (ISGs) and mediating signals downstream of IFN-γ. Although ectopic expression experiments have suggested an inhibitory function of IRF-1 against infection of alphaviruses in cell culture, its role in vivo remains unknown. Here, we infected Irf1 −/− mice with two distantly related arthritogenic alphaviruses, chikungunya virus (CHIKV) and Ross River virus (RRV), and assessed the early antiviral functions of IRF-1 prior to induction of adaptive B and T cell responses. IRF-1 expression limited CHIKV-induced foot swelling in joint-associated tissues and prevented dissemination of CHIKV and RRV at early time points. Virological and histological analyses revealed greater infection of muscle tissues in Irf1 −/− mice than in wild-type mice. The antiviral actions of IRF-1 appeared to be independent of the induction of type I IFN or the effects of type II and III IFNs but were associated with altered local proinflammatory cytokine and chemokine responses and differential infiltration of myeloid cell subsets. Collectively, our in vivo experiments suggest that IRF-1 restricts CHIKV and RRV infection in stromal cells, especially muscle cells, and that this controls local inflammation and joint-associated swelling. IMPORTANCE Interferon regulatory factor 1 (IRF-1) is a transcription factor that regulates the expression of a broad range of antiviral host defense genes. In this study, using Irf1 −/− mice, we investigated the role of IRF-1 in modulating pathogenesis of two related arthritogenic alphaviruses, chikungunya virus and Ross River virus. Our studies show that IRF-1 controlled alphavirus replication and swelling in joint-associated tissues within days of infection. Detailed histopathological and virological analyses revealed that IRF-1 preferentially restricted CHIKV infection in cells of nonhematopoietic lineage, including muscle cells. The antiviral actions of IRF-1 resulted in decreased local inflammatory responses in joint-associated tissues, which prevented immunopathology.

P.1.04 Impacts of type I interferons (IFN-α andIFN-τ) and type II interferon (IFN-γ) on the kynurenine pathway in human uninfected or HIV-1 infected macrophages

2005 ◽  
Vol 15 ◽  
pp. S6
Author(s):  
B. Manéglier ◽  
C. Rogez-Kreuz ◽  
O. Spreux-Varoquaux ◽  
N. Dereuddre-Bosquet ◽  
J. Marlal ◽  
...  
Keyword(s):  
Kynurenine Pathway ◽  
Type I Interferons ◽  
Type I ◽  
Type Ii ◽  
Ifn Γ ◽  
Hiv 1

scholarly journals Two Modes of the Axonal Interferon Response Limit Alphaherpesvirus Neuroinvasion

mBio ◽  
2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Ren Song ◽  
Orkide O. Koyuncu ◽  
Todd M. Greco ◽  
Benjamin A. Diner ◽  
Ileana M. Cristea ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Body ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Long Distance ◽  
Peripheral Tissues ◽  
Ifn Γ ◽  
Simplex Virus

ABSTRACT Infection by alphaherpesviruses, including herpes simplex virus (HSV) and pseudorabies virus (PRV), typically begins at epithelial surfaces and continues into the peripheral nervous system (PNS). Inflammatory responses are induced at the infected peripheral site prior to invasion of the PNS. When the peripheral tissue is first infected, only the innervating axons are exposed to this inflammatory milieu, which includes the interferons (IFNs). The fundamental question is how do PNS cell bodies respond to these distant, potentially damaging events experienced by axons. Using compartmented cultures that physically separate neuron axons from cell bodies, we found that pretreating isolated axons with beta interferon (IFN-β) or gamma interferon (IFN-γ) significantly diminished the number of herpes simplex virus 1 (HSV-1) and PRV particles moving in axons toward the cell bodies in a receptor-dependent manner. Exposing axons to IFN-β induced STAT1 phosphorylation (p-STAT1) only in axons, while exposure of axons to IFN-γ induced p-STAT1 accumulation in distant cell body nuclei. Blocking transcription in cell bodies eliminated antiviral effects induced by IFN-γ, but not those induced by IFN-β. Proteomic analysis of IFN-β- or IFN-γ-treated axons identified several differentially regulated proteins. Therefore, unlike treatment with IFN-γ, IFN-β induces a noncanonical, local antiviral response in axons. The activation of a local IFN response in axons represents a new paradigm for cytokine control of neuroinvasion. IMPORTANCE Neurons are highly polarized cells with long axonal processes that connect to distant targets. PNS axons that innervate peripheral tissues are exposed to various situations that follow infection, inflammation, and damage of the tissue. After viral infection in the periphery, axons represent potential front-line barriers to PNS infection and damage. Indeed, most viral infections do not spread to the PNS, yet the mechanisms responsible are not well studied. We devised an experimental system to study how axons respond to inflammatory cytokines that would be produced by infected tissues. We found that axons respond differentially to type I and type II interferons. The response to type I interferon (IFN-β) is a rapid axon-only response. The response to type II interferon (IFN-γ) involves long-distance signaling to the PNS cell body. These responses to two interferons erect an efficient and rapid barrier to PNS infection.

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