Academic literature on the topic 'IFN-stimulated gene'
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Journal articles on the topic "IFN-stimulated gene"
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Routes, J. M., H. Li, S. T. Bayley, S. Ryan, and D. J. Klemm. "Inhibition of IFN-stimulated gene expression and IFN induction of cytolytic resistance to natural killer cell lysis correlate with E1A-p300 binding." Journal of Immunology 156, no. 3 (February 1, 1996): 1055–61. http://dx.doi.org/10.4049/jimmunol.156.3.1055.
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Abstract Treatment of target cells with IFN induces resistance to NK cell lysis. This process is blocked by expression of E1A gene products in adenovirus (Ad)-infected and Ad-transformed cells. We compared the ability of adenovirus serotype 5 (Ad5) E1A exon 1 mutants to inhibit the induction of cytolytic resistance by IFN and block IFN-stimulated gene expression with their capacity to bind the cellular proteins p105 (retinoblastoma gene product), p107, and p300. E1A mutants that did not express conserved region 3 (CR3; residues 138-184) or contained deletions in the nonconserved regions between residues 26-35 or 86-120, bound p105, p107, and p300 and were not impaired in their capacity to block IFN-stimulated gene expression or IFN's induction of cytolytic resistance. E1A mutants with deletions in CR2 (residues 121-138) could not bind p105 or p107, but blocked IFN-stimulated gene expression and IFN's induction of cytolytic resistance. In contrast, mutants in CR1 or the N-terminal nonconserved region (residues 2, 4-25, and 48-60), which define E1A's binding site for p300, were unable to block either IFN-stimulated gene expression or IFN's induction of cytolytic resistance. We conclude that E1A's capacity to block both IFN-stimulated gene expression and IFN's induction of cytolytic resistance appears to be transduced through a pathway that involves E1A-p300 binding. The capacity of E1A to block IFN's induction of cytolytic resistance is probably secondary to E1A's more general ability to inhibit IFN-stimulated gene expression.
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Cui, Xue-Fan, Tadaatsu Imaizumi, Hidemi Yoshida, Ernest C. Borden, and Kei Satoh. "Retinoic acid-inducible gene-I is induced by interferon-γ and regulates the expression of interferon-γ stimulated gene 15 in MCF-7 cells." Biochemistry and Cell Biology 82, no. 3 (June 1, 2004): 401–5. http://dx.doi.org/10.1139/o04-041.
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Retinoic acid-inducible gene-І (RIG-І) is a member of the DExH box family proteins, which have diverse roles in regulation of gene expression and cellular functions. We found RIG-I mRNA and protein were expressed in MCF-7 human breast cancer cells stimulated with interferon-γ (IFN-γ). This effect of IFN-γ was observed in concentration- and time-dependent manners, and IFN-γ also induced promoter activity of RIG-I. Transfection of GFP-RIG-I cDNA into MCF-7 cells resulted in the expression of RIG-I protein in cytoplasm. Overexpression of RIG-I induced the upregulation of IFN-γ stimulated gene 15, which has the potential to amplify the immunomodulatory effects. We conclude that IFN-γ induces the expression of RIG-I, which may play a role in the immunological effects of IFN-γ.Key words: retinoic acid-inducible gene-I, interferon-γ, interferon-γ stimulated gene 15.
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Haque, S. J., and B. R. Williams. "Identification and characterization of an interferon (IFN)-stimulated response element-IFN-stimulated gene factor 3-independent signaling pathway for IFN-alpha." Journal of Biological Chemistry 269, no. 30 (July 1994): 19523–29. http://dx.doi.org/10.1016/s0021-9258(17)32200-7.
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Lew, D. J., T. Decker, I. Strehlow, and J. E. Darnell. "Overlapping elements in the guanylate-binding protein gene promoter mediate transcriptional induction by alpha and gamma interferons." Molecular and Cellular Biology 11, no. 1 (January 1991): 182–91. http://dx.doi.org/10.1128/mcb.11.1.182-191.1991.
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The gene encoding a 67-kDa cytoplasmic guanylate-binding protein (GBP) is transcriptionally induced in cells exposed to interferon of either type I (alpha interferon [IFN-alpha] or type II (IFN-gamma). The promoter of the GBP gene was cloned and found to contain an IFN-alpha-stimulated response element, which mediated the response of the GBP gene to IFN-alpha. On the basis of transfection experiments with recombinant plasmids, two different elements were delineated. Both were required to obtain the maximal response of the GBP gene to IFN-gamma: the IFN-alpha-stimulated response element and an overlapping element termed the IFN-gamma activation site. Different proteins that act on each element were investigated, and their possible involvement in IFN-gamma-induced transcriptional regulation is discussed.
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Lew, D. J., T. Decker, I. Strehlow, and J. E. Darnell. "Overlapping elements in the guanylate-binding protein gene promoter mediate transcriptional induction by alpha and gamma interferons." Molecular and Cellular Biology 11, no. 1 (January 1991): 182–91. http://dx.doi.org/10.1128/mcb.11.1.182.
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The gene encoding a 67-kDa cytoplasmic guanylate-binding protein (GBP) is transcriptionally induced in cells exposed to interferon of either type I (alpha interferon [IFN-alpha] or type II (IFN-gamma). The promoter of the GBP gene was cloned and found to contain an IFN-alpha-stimulated response element, which mediated the response of the GBP gene to IFN-alpha. On the basis of transfection experiments with recombinant plasmids, two different elements were delineated. Both were required to obtain the maximal response of the GBP gene to IFN-gamma: the IFN-alpha-stimulated response element and an overlapping element termed the IFN-gamma activation site. Different proteins that act on each element were investigated, and their possible involvement in IFN-gamma-induced transcriptional regulation is discussed.
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Komatsu, Takayuki, Kenji Takeuchi, Junko Yokoo, Yukie Tanaka, and Bin Gotoh. "Sendai Virus Blocks Alpha Interferon Signaling to Signal Transducers and Activators of Transcription." Journal of Virology 74, no. 5 (March 1, 2000): 2477–80. http://dx.doi.org/10.1128/jvi.74.5.2477-2480.2000.
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ABSTRACT We demonstrate here that Sendai virus (SeV) blocks alpha interferon (IFN-α) signaling to signal transducers and activators of transcription (STATs) in HeLa cells. IFN-α-stimulated tyrosine phosphorylation of STATs and subsequent formation of the IFN-stimulated gene factor 3 transcription complex were inhibited in SeV-infected cells, resulting in inefficient induction of IFN-stimulated gene products. None of the components of the signaling pathway—type I IFN receptor subunits Jak1, Tyk2, Stat1, Stat2, and p48—was degraded. Moreover, tyrosine phosphorylation of Jak1 in response to IFN-α was unaffected at the early phase of infection, suggesting that oligomerization of the receptor subunits proceeded normally. In contrast to Jak1, IFN-α-stimulated tyrosine phosphorylation of Tyk2 was partially inhibited. Therefore, this partial inhibition of activation of Tyk2 probably contributes to the subsequent failure in the activation of STATs.
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Nguyen, Nam V., James T. Tran, and David Jesse Sanchez. "HIV blocks Type I IFN signaling through disruption of STAT1 phosphorylation." Innate Immunity 24, no. 8 (October 3, 2018): 490–500. http://dx.doi.org/10.1177/1753425918803674.
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This study investigates the modulation of Type I IFN induction of an antiviral state by HIV. IFNs, including IFN-α, are key innate immune cytokines that activate the JAK/STAT pathway leading to the expression of IFN-stimulated genes. IFN-stimulated gene expression establishes the antiviral state, limiting viral infection in IFN-α-stimulated microenvironments. Our previous studies have shown that HIV proteins disrupt the induction of IFN-α by degradation of IFN-β promoter stimulator-1, an adaptor protein for the up-regulation and release of IFN-α into the local microenvironment via the retinoic acid-inducible gene 1-like receptor signaling pathway. However, IFN-α is still released from other sources such as plasmacytoid dendritic cells via TLR-dependent recognition of HIV. Here we report that the activation of the JAK/STAT pathway by IFN-α stimulation is disrupted by HIV proteins Vpu and Nef, which both reduce IFN-α induction of STAT1 phosphorylation. Thus, HIV would still be able to avoid antiviral protection induced by IFN-α in the local microenvironment. These findings show that HIV blocks multiple signaling points that would lead to the up-regulation of IFN-stimulated genes, allowing more effective replication in IFN-α-rich environments.
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Valente, Anthony J., Jing-feng Xie, Margaret A. Abramova, Ulrich O. Wenzel, Hanna E. Abboud, and Dana T. Graves. "A Complex Element Regulates IFN-γ-Stimulated Monocyte Chemoattractant Protein-1 Gene Transcription." Journal of Immunology 161, no. 7 (October 1, 1998): 3719–28. http://dx.doi.org/10.4049/jimmunol.161.7.3719.
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Abstract Monocyte chemoattractant protein-1 (MCP-1) is induced in chronic osseous inflammation, and is temporally and spatially correlated with monocyte recruitment. We investigated the mechanism of MCP-1 regulation in a human osteoblastic cell line in response to IFN-γ, a potent mediator of the immune inflammatory response. Nuclear run-on and stability studies demonstrated that IFN-γ stimulated MCP-1 transcription and did not enhance mRNA stabilization. Using MCP-1 promoter/reporter gene constructs, we determined that IFN-γ-enhanced MCP-1 transcription is regulated by a 29-bp element located at −227 relative to the ATG start codon. This element contains a 13-bp CT-rich sequence (GCTTCCCTTTCCT) adjacent to a IFN-γ activation site (GAS). Since deletion of the CT sequence enhanced both the magnitude and duration of IFN-γ-stimulated, GAS-mediated transcription, we have termed it the IFN response-inhibitory sequence (IRIS). The combined IRIS/GAS sequence is highly conserved in mouse, rat, and bovine MCP-1 genes. In gel-shift assays, nuclear extracts from IFN-γ-stimulated osteoblastic cells formed two specific inducible bands with labeled IRIS/GAS DNA. Both bands were supershifted by anti-STAT1 Abs, but not by Abs to STAT2, p48(ISGF-3γ), IFN-regulatory factor-1, or IFN-regulatory factor-2. Formation of one of the bands required the presence of the IRIS moiety. IRIS/GAS DNA also formed a number of specific complexes with constitutively expressed factors, none of which were affected by the above Abs. These studies establish a mechanism for IFN-γ-stimulated MCP-1 expression and identify a complex element that regulates MCP-1 gene transcription.
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Kanda, K., T. Decker, P. Aman, M. Wahlström, A. von Gabain, and B. Kallin. "The EBNA2-related resistance towards alpha interferon (IFN-alpha) in Burkitt's lymphoma cells effects induction of IFN-induced genes but not the activation of transcription factor ISGF-3." Molecular and Cellular Biology 12, no. 11 (November 1992): 4930–36. http://dx.doi.org/10.1128/mcb.12.11.4930-4936.1992.
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Transfection of a plasmid encoding the Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) gene confers resistance to the antiproliferative effect of alpha interferon (IFN-alpha) in EBV-negative U968 cells (P. Aman and A. von Gabain, EMBO J. 9:147-152, 1990). We studied the expression of IFN-stimulated genes (ISGs) in two pairs of Burkitt's lymphoma cell lines, differing in the expression of the putative immortalizing gene of EBV, EBNA2. In EBNA2-expressing cells, the induction of four ISGs by IFN-alpha was strongly reduced or, in some cases, abolished. Chloramphenicol acetyltransferase reporter gene constructs containing different IFN-stimulated response elements were transfected into EBNA2-negative and EBNA2-positive cells. Induction of chloramphenicol acetyltransferase activity by IFN was impaired in EBNA2-positive cells. Also, a reporter gene construct driven by an IFN-gamma-sensitive promoter element was affected. However, as revealed by gel shift assays, EBNA2-positive and EBNA2-negative cells exhibited a nearly identical pattern of IFN-stimulated response element-binding proteins. Most important, activation of the factor ISGF-3, which previously has been shown to be required and sufficient for transcriptional activation of IFN-induced genes, was not inhibited in IFN-resistant cells expressing EBNA2. The mechanism of the EBNA2-related IFN resistance seems to be distinct both from the resistance mediated by hepatitis virus and adenovirus gene products and from the IFN resistance in Daudi cell variants. In these three cases, the transcriptional block of IFN-induced genes is due to inhibition of ISGF-3 activation and binding. Our data suggest that the EBNA2-related IFN resistance in Burkitt's lymphoma cells acts downstream of the activation of ISGF-3.
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Kanda, K., T. Decker, P. Aman, M. Wahlström, A. von Gabain, and B. Kallin. "The EBNA2-related resistance towards alpha interferon (IFN-alpha) in Burkitt's lymphoma cells effects induction of IFN-induced genes but not the activation of transcription factor ISGF-3." Molecular and Cellular Biology 12, no. 11 (November 1992): 4930–36. http://dx.doi.org/10.1128/mcb.12.11.4930.
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Transfection of a plasmid encoding the Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) gene confers resistance to the antiproliferative effect of alpha interferon (IFN-alpha) in EBV-negative U968 cells (P. Aman and A. von Gabain, EMBO J. 9:147-152, 1990). We studied the expression of IFN-stimulated genes (ISGs) in two pairs of Burkitt's lymphoma cell lines, differing in the expression of the putative immortalizing gene of EBV, EBNA2. In EBNA2-expressing cells, the induction of four ISGs by IFN-alpha was strongly reduced or, in some cases, abolished. Chloramphenicol acetyltransferase reporter gene constructs containing different IFN-stimulated response elements were transfected into EBNA2-negative and EBNA2-positive cells. Induction of chloramphenicol acetyltransferase activity by IFN was impaired in EBNA2-positive cells. Also, a reporter gene construct driven by an IFN-gamma-sensitive promoter element was affected. However, as revealed by gel shift assays, EBNA2-positive and EBNA2-negative cells exhibited a nearly identical pattern of IFN-stimulated response element-binding proteins. Most important, activation of the factor ISGF-3, which previously has been shown to be required and sufficient for transcriptional activation of IFN-induced genes, was not inhibited in IFN-resistant cells expressing EBNA2. The mechanism of the EBNA2-related IFN resistance seems to be distinct both from the resistance mediated by hepatitis virus and adenovirus gene products and from the IFN resistance in Daudi cell variants. In these three cases, the transcriptional block of IFN-induced genes is due to inhibition of ISGF-3 activation and binding. Our data suggest that the EBNA2-related IFN resistance in Burkitt's lymphoma cells acts downstream of the activation of ISGF-3.
Dissertations / Theses on the topic "IFN-stimulated gene"
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Wu, Nannan. "Novel antiviral mechanism of IFN-stimulated gene 20(ISG20) via translational suppression." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSEN005/document.
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La réponse interféron est une réponse antivirale complexe qui, après la détection de pathogènes par des PRR (récepteurs de motifs associés aux pathogènes), conduit à l’induction de centaines de gènes appelés ISG (gènes stimulés par l’interféron). Dans la littérature, il existe plusieurs ISG capables de s’opposer à l’infection virale ; cependant le rôle antiviral précis d’un grand nombre d’entre eux reste inconnu ou mal caractérisé. Pendant ma thèse, je me suis concentré sur la caractérisation d’ISG20 pendant la réplication de deux virus, VSV et le VIH-1. La protéine ISG20 a été décrite au préalable comme une exonucléase 3’-5’ antivirale en agissant sur la dégradation directe du génome viral. Cependant, la diminution de la quantité d’ARN viraux liée à ISG20 était controversée.Afin de mieux comprendre le mécanisme par lequel ISG20 interfère avec la réplication virale, j’ai construit plusieurs mutants d’ISG20. Les résultats obtenus indiquent que l’activité antivirale d’ISG20 ne repose pas uniquement sur sa capacité à dégrader l’ARN, puisque plusieurs mutants ont perdu leurs propriétés antivirales malgré une robuste activité RNase in vitro.Mes résultats montrent qu’ISG20 peut bloquer la réplication virale en bloquant la traduction. Dans les cellules exprimant ISG20, ce blocage intervient à la fois pendant l’infection virale et lors de l’expression ectopique de gènes rapporteurs. Les résultats que nous avons obtenus indiquent que la protéine ISG20 affecte la traduction qu’elle soit cap- ou IRES-dépendant. Cette inhibition de la traduction est très probablement indépendante de l’initiation.Afin d’étayer le rôle antiviral d’ISG20 pendant l’infection virale, des souris invalidées pour isg20 (-/-) ont été générées et leur capacité à supporter l’infection par VSV in vivo a été analysée. Les résultats obtenus impliquent clairement ISG20 dans le contrôle naturel de la propagation virale in vivo, confirmant nos données ex vivo.Dans l’ensemble, les données obtenues pendant ma thèse indiquent qu’ISG20 est un important facteur antiviral et mettent en évidence un nouveau mécanisme d’inhibition virale où ISG20 interfère avec la traduction d’ARNm viralInterferons specify a complex antiviral response that upon the detection of pathogens through various cellular pattern-recognition receptors (PRRs) lead to the induction of hundreds of genes named interferon-stimulated genes (ISGs). Several ISGs have been reported to restrict viral infection, however the antiviral role/s of many of them remains either unknown or poorly characterized. During my thesis I have focused on the characterization of ISG20 during the replication of two viruses, VSV and HIV-1. ISG20 had been previously identified as an antiviral 3’-5’ exonuclease and was thought to act by directly degrading viral genomes. However, the decrease in viral RNAs specified by ISG20 was controversial. To gather further insights into the mechanism with which ISG20 interfered with viral replication, I constructed several mutants of ISG20. The results we have obtained indicated that the antiviral activity of ISG20 does not solely rely on it's the ability of ISG20 to degrade RNA, as several mutants were identified that lost their antiviral properties despite a robust RNase capacity in vitro.We have found here that ISG20 could block viral replication through a block in translation. This block occurred both during viral infection as well as during the ectopic expression of reporter genes in ISG20-expressing cells. The results we have obtained indicate that ISG20 affects both cap- and IRES-mediated translation in a manner that is very likely independent from translation initiation.To substantiate the antiviral role of ISG20 during viral infection, knock-out isg20 -/- mice were generated and then analyzed for their ability to support VSV infection in vivo. The results obtained, clearly implicate ISG20 in the natural control of viral spread in vivo, strongly supporting our data ex vivo.Overall, the data obtained during my thesis indicate that ISG20 is an important antiviral factor and shed light on a novel mechanism of viral inhibition whereby ISG20 interferes with viral mRNA translation
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SEVERA, MARTINA. "Toll-like receptor-mediated induction of type I interferons promotes functional modifications and changing in the gene expression profile along dendritic cell maturation." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2009. http://hdl.handle.net/2108/979.
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Le cellule dendritiche (DC) sono considerate le principali cellule presentanti l`antigene per la loro straordinaria capacità di modulare sia la risposta innata che quella adattativa. Il riconoscimento dei patogeni da parte dei Toll-like Receptors (TLR) induce la maturazione delle DC e la successiva produzione di citochine necessarie per la regolazione della risposta immunitaria. Tra le citochine prodotte, gli Interferoni di tipo I (IFN) svolgono un ruolo chiave nella regolazione della risposta immunitaria in quanto, oltre a regolare la proliferazione, differenziamento e maturazione di diverse popolazioni leucocitarie, sono in grado di modulare diverse funzioni delle DC agendo in maniera autocrina e paracrina.
Sulla base di queste evidenze gli obiettivi principali di questa tesi sono stati la caratterizzazione del profilo di espressione dei vari sottotipi degli IFN di tipo I indotti nelle DC in seguito ad infezione virale o attivazione dei TLR e l’analisi delle modificazioni funzionali e dei cambiamenti nel trascrittoma IFN-mediati durante la maturazione delle DC.
I risultati ottenuti dimostrano:
- che sia l`infezione delle DC con il virus dell`Influenza di tipo A (Flu) o con il virus Sendai (SV) che la stimolazione del TLR3 e TLR4 con i rispettivi agonisti, l`acido polinosinic-poliacitidilico [poly(I:C)] e il lipopolisaccaride (LPS), inducono un`espressione selettiva dei vari sottotipi degli IFN di tipo I. In particolare, mentre tutti gli IFN di tipo I analizzati vengono indotti in seguito ad infezione virale, l`attivazione del TLR3 e TLR4 promuove soprattutto l`espressione dell` IFN-beta suggerendo la possibilità che questa citochina abbia un ruolo cruciale nel processo di maturazione delle DC;
- l’esistenza di uno specifico set di geni, coinvolti nelle risposte immuni anti-virali o anti-batteriche, specificamente indotto dalla produzione di IFN-beta durante la maturazione delle DC indotta dal trattamento con LPS;
- che fra i geni IFN-regolati è presente Viperin (virus inhibitory protein, endoplasmic reticulum-associated, interferon-beta inducible), una molecola che possiede un’attività antivirale il cui ruolo non è stato completamente chiarito. La stimolazione del TLR3 e del TLR4 induce alti livelli di espressione di Viperin tramite il pathway intracellulare che coinvolge TRIF, TBK1 e il recettore per il type I IFN (IFNalfa/betaR), mentre l`espressione di Viperin indotta dall`infezione con SV è TLR-independente e coinvolge l`RNA elicasi Retinoic acid-inducible gene (RIG-I). Abbiamo inoltre identificato come fattore trascrizionale chiave per l`induzione di Viperin il complesso IFN-stimulated gene factor (ISGF)-3, la cui azione viene bloccata dal repressore trascrizionale positive regulatory domain I-binding factor 1 (PRDI-BF1, anche chiamato BLIMP1) in grado di competere con ISGF-3 per i siti IFN stimulatory and regulatory element (ISRE) presenti all`interno della regione promotrice del gene Viperin.
- il gene codificante per il TLR7 è indotto in maniera IFN-dipendente durante la maturazione delle DC mediata da LPS. Sono stati esaminati i meccanismi responsabili dell`espressione del TLR7 identificando nel fattore trascrizionale IRF-1, i cui siti di legame sono presenti nel promotore del TLR7, il principale attivatore. Inoltre, abbiamo dimostrato che il “priming” con IFN- esogeno delle DC immature, che esprimono solo il TLR8, induce un TLR7 funzionalmente attivo. Infatti, l’utilizzo di un agonista specifico per il TLR7 (3M-001) induce la maturazione delle DC caratterizzata dall`espressione di molecole costimolatorie e dalla produzione di citochine pro-infiammatorie e regolatorie.
L’insieme dei nostri dati suggerisce che il rilascio di IFN di tipo I, indotto dalla stimolazione del TLR4, induce nelle DC uno specifico programma trascrizionale in grado di amplificare l`espressione di “sensori” intracellulari per differenti patogeni e rispondere in questo modo correttamente e combinatoriamente sia alle infezioni virali che a quelle batteriche.
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Chen, Jiun-Wei, and 陳俊瑋. "The Mechanism Research on Inhibition of Japanese Encephalitis Virus Replication by IFN-stimulated Gene 15." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/61984377652564037754.
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碩士國立彰化師範大學
生物技術研究所
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Type I interferon (IFN)-α and β play an important role in innate immunity to against viral infection through the induction of numerous IFN-stimulated genes (ISGs). IFN- stimulated gene 15 (ISG15), a ubiquitin-like protein, is rapidly induced by IFN-α/β has been reported to be involved to inhibit the replication of NDV, Influenza A Virus, HIV-1, Sindbis Virus, and HSV-1. Japanese encephalitis virus (JEV) that is a mosquito-borne neurotropic flavivirus causes severe central nerve system diseases. We intend to investigate the potential antiviral ability of ISG15 against the JEV infection. Overexpression of ISG15 in human neuronal medulloblastoma TE671 cells significantly reduced the level of JEV-induced cytopathic effect and inhibited the JEV replication about 10 to 100 folds at 24, 48 and 72 hours post infection. In addition, the ISG15 expression reduced the JEV-induced apoptosis and inhibited the NF-κB and p53 activities. Interestingly, the expression of ISG15 increased the responses of JEV-infected cells to the IFN-β treatment, such as the activation of interferon stimulatory response element (ISRE)-luciferase reporter, and the gene expression of IL-6, IL-8, PKR and OAS. Furthermore, Western blotting revealed that the expression of ISG15 significantly increased the phosphorylation level of IRF-3, JAK2 and STAT1 in the JEV-infected cells. Confocal imaging indicated that the translocation of the transcription factors IRF-3 and STAT-1 into nucleus was found in the ISG15- expressing cells post the JEV infection, but in the JEV-infected mock cells. The results elucidated the mechanism of the anti-JEV ability by ISG15, being useful for the clinical application in the treatment against the JEV infection.
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Cui, Dan. "Analysis of a Non-canonical Antiviral Mechanism in West Nile Virus-infected Mouse Cells." 2017. http://scholarworks.gsu.edu/biology_diss/192.
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Upon viral infection, host cells produce type I interferon (IFN), which activates the JAK-STAT signaling pathway and induces the expression of hundreds of interferon-stimulated genes (ISGs) to establish an antiviral state. In West Nile virus (WNV)-infected cells, the JAK-STAT signaling pathway is blocked by viral proteins. However, the expression of a subset of ISGs, which includes 2¢-5¢-oligoadenylate synthetase 1a (Oas1a), Oas1b, interferon regulatory factor 7 (Irf7), Mx1, and interferon-induced proteins with tetratricopeptide repeats 1 (Ifit1), is still upregulated by an IFN-independent mechanism in WNV-infected mouse embryonic fibroblasts (MEFs). Studies in cells with one or more components of RNA-sensing pathway knocked out showed that the alternative ISG upregulation is activated through RIG-I or MDA5, and the downstream adaptor IPS-1. In cells with IRF3, 5 and 7 knocked out, the alternative ISG upregulation by WNV infection is reduced but not eliminated. As an initial means of discovering the transcription factors involved in this non-canonical ISG upregulation, the critical regulatory regions in the promoters of two representative ISGs, Oas1b and Ifit1, were mapped using a dual luciferase assay system with a NanoLuc luciferase promoter reporter in WNV-infected Ifnar1-/- MEFs. The region from -299 to -28 in the Oas1b promoter, and the region from -192 to -50 in the Ifit1 promoter were identified as being important for upregulating non-canonical gene expression after WNV infection. Fine mapping identified enhancer and repressor sub-regions as well as transcription factor binding sites (TFBSs) putatively involved in the IFN-independent antiviral mechanism. Mutation of one identified TFBS in the ISG promoters reduced Oas1b and Ifit1 promoter activities. In electrophoretic mobility shift assays (EMSAs), a unique band, which was detected in WNV-infected but not in mock-infected Ifnar1-/- MEF nuclear extracts, was not observed when a probe with the identified TFBS mutated was used, suggesting that a unique complex forms at the identified TFBS when it is in the context of the adjacent flanking regions. The unique complex appears to contain NF-κB components and IRF3, IRF5 or IRF7. Our findings provide new insights into the mechanism involved in non-canonical upregulation of ISGs after WNV infection.
Book chapters on the topic "IFN-stimulated gene"
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Aiman, Ayesha, Seemi Farhat Basir, and Asimul Islam. "Interferons Horizon Therapeutics." In Interferon - Immune Metabolism [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.104718.
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Interferons (IFNs) are a family of multi-functional proteins, called cytokines, that are produced by immune cells such as leukocytes, natural killer (NK) cells, macrophages, fibroblasts, and epithelial cells. The minute amount of these α-helical glycoproteins, produced by mammalian cells, are firm components of the innate arm of the immune system providing rapid and broad protection against numerous types of invading pathogens. Interferons, from their discovery in the 19th century, have always held out a promise of important clinical utility first as an antiviral agent and more recently holding anti-inflammatory and regenerative effects for treating various neurological diseases such as multiple sclerosis, encephalopathies, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), etc. IFNs elicit anti-viral and anti-inflammatory properties by inducing transcription of multiple IFN stimulated genes (ISG), a response that is partly mediated by Interferon regulatory factors (IRFs). This chapter provides a brief introduction of the interferon system as well as an in-depth assessment of the interferon signature and the various assay procedures for synthesizing non-natural interferon analogs for structural analysis, which may be helpful in designing improved products and act as a diagnostic tool for neurodegenerative disorders.
Reports on the topic "IFN-stimulated gene"
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Splitter, Gary, Zeev Trainin, and Yacov Brenner. Lymphocyte Response to Genetically Engineered Bovine Leukemia Virus Proteins in Persistently Lymphocytic Cattle from Israel and the U.S. United States Department of Agriculture, July 1995. http://dx.doi.org/10.32747/1995.7570556.bard.
Full textAbstract:
The goal of this proposal was to identify proteins of BLV recognized by lymphocyte subpopulations and determine the contribution of these proteins to viral pathogenesis. Our hypothesis was that BLV pathogenesis is governed by the T-cell response and that the immune system likely plays an important role in controlling the utcome of infection. Our studies presented in ths final report demonstrate that T cell competency declines with advancing stages of infection. Dramatic differences were observed in lymphocyte proliferation to recombinant proteins encoded by BLV gag (p12, p15, and p24) and env (gp30 and gp15) genes in different disease stages. Because retroviruses are known to mutate frequently, examinatin of infected cattle from both Israel and the United States will likely detect variability in the immune response. This combined research approach provides the first opportunity to selectively address the importance of T-cell proliferation to BLV proteins and cytokines produced during different stages of BLV infection. Lack of this information regarding BLV infection has hindered understanding lympocyte regulation of BLV pathogenesis. We have developed the essential reagents necessary to determine the prominence of different lymphocyte subpopulations and cytokines produced during the different disease stages within the natural host. We found that type 1 cytokines (IL-2 and IFN-g) increased in PBMCs from animals in early disease, and decreasd in PBMCs from animals in late disease stages of BLV infection, while IL-10, increased with disease progression. Recently, a dichotomy between IL-12 and IL-10 has emerged in regards to progression of a variety of diseases. IL-12 activates type 1 cytokine production and has an antagonistic effect on type 2 cytokines. Here, using quantitative competitive PCR, we show that peripheral blood mononuclear cells from bovine leukemia virus infected animals in the alymphocytotic disease stage express increased amount of IL-12 p40 mRNA. In contrast, IL-12 p40 mRNA expression by PL animals was significantly decreased compared to normal and alymphocytotic animals. To examine the functions of these cytokines on BLV expression, BLV tax and pol mRNA expression and p24 protein production were quantified by competitive PCR, and by immunoblotting, respectively. IL-10 inhibited BLV tax and pol mRNA expression by BLV-infected PBMCs. In addition, we determined that macrophages secret soluble factor(s) that activate BLV expression, and that secretion of the soluble factor(s) could be inhibited by IL-10. In contrast, IL-2 increased BLV tax and pol mRNA, and p24 protein production. These findings suggest that macrophages have a key role in regulating BLV expression, and IL-10 produced by BLV-infected animals in late disease stages may serve to control BLV expression, while IL-2 in the early stage of disease may activate BLV expression. PGE2 is an important immune regulator produced only by macrophages, and is known to facilitate HIV replication. We hypothesized that PGE2 may regulate BLV expression. Here, we show that cyclooxygenase-2 (COX-2) mRNA expression was decreased in PBMCs treated with IL-10, while IL-2 enhanced COX-2 mRNA expression. In contrast, addition of PGE2 stimulated BLV tax and pol mRNA expression. In addition, the specific COX-2 inhibitor, NS-398, inhibited BLV expression, while addition of PGE2 increased BLV tax expression regardless of NS-398. These findings suggest that macrophage derived cyclooxygenase -2 products, such as PGE2, may regulate virus expression and disease rogression in BLV infection, and that cytokines (IL-2 and IL-10) may regulate BLV expression through PGE2 production.