The Experts below are selected from a list of 18363 Experts worldwide ranked by ideXlab platform
Stefanie N Vogel - One of the best experts on this subject based on the ideXlab platform.
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transcriptional regulation of lipopolysaccharide lps induced toll like receptor tlr expression in murine macrophages role of Interferon Regulatory Factors 1 irf 1 and 2 irf 2
Journal of Endotoxin Research, 2006Co-Authors: Quan M Nhu, Natalia Cuesta, Stefanie N VogelAbstract:Activation of TLRs is most closely associated with induction of pro-inflammatory gene expression; however, expression of many other genes, including the TLR genes themselves, has also been shown to be modulated following TLR engagement. A large family of nuclear transcription Factors, the Interferon Regulatory Factors (IRFs), have been implicated in TLR signaling leading to pro-inflammatory gene expression. Given that IRF-1 and IRF-2 counter-regulate the transcriptional activity of many genes, we hypothesized that IRF-1 and IRF-2 might also regulate TLR gene expression following LPS stimulation of murine macrophages. mRNA derived from medium- or LPS-treated primary peritoneal macrophages was analyzed for TLR gene expression using quantitative real-time PCR. In wild-type macrophages, LPS up-regulated expression of TLRs 1-3 and 6-9 steady-state mRNA, while TLR4 mRNA was modestly down-regulated. IRF-2(-/-) macrophages responded to LPS with dysregulated expression of TLR3, TLR4, and TLR5 mRNA, whereas IRF-1 deficiency dampened LPS-induced mRNA expression for TLR3, TLR6, and TLR9. Functional studies revealed aberrant TLR3 signaling in IRF-2(-/-) macrophages. Collectively, these findings reveal an additional level of complexity associated with TLR transcriptional regulation and suggest that the trans-acting Factors, IRF-1 and IRF-2, contribute to the innate immune response to infections by regulating TLR gene expression.
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transcriptional regulation of lipopolysaccharide lps induced toll like receptor tlr expression in murine macrophages role of Interferon Regulatory Factors 1 irf 1 and 2 irf 2
Journal of Endotoxin Research, 2006Co-Authors: Natalia Cuesta, Stefanie N VogelAbstract:Activation of TLRs is most closely associated with induction of pro-inflammatory gene expression; however, expression of many other genes, including the TLR genes themselves, has also been shown to be modulated following TLR engagement. A large family of nuclear transcription Factors, the Interferon Regulatory Factors (IRFs), have been implicated in TLR signaling leading to pro-inflammatory gene expression. Given that IRF-1 and IRF-2 counter-regulate the transcriptional activity of many genes, we hypothesized that IRF-1 and IRF-2 might also regulate TLR gene expression following LPS stimulation of murine macrophages. mRNA derived from medium- or LPS-treated primary peritoneal macrophages was analyzed for TLR gene expression using quantitative real-time PCR. In wild-type macrophages, LPS up-regulated expression of TLRs 1—3 and 6—9 steady-state mRNA, while TLR4 mRNA was modestly downregulated. IRF-2—/ — macrophages responded to LPS with dysregulated expression of TLR3, TLR4, and TLR5 mRNA, whereas IRF-1 def...
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role of Interferon and Interferon Regulatory Factors in early protection against venezuelan equine encephalitis virus infection
Virology, 1999Co-Authors: Franziska B Grieder, Stefanie N VogelAbstract:To investigate the role of type I Interferon (IFN) and its Regulatory transacting proteins, Interferon Regulatory Factors (IRF-1 and IRF-2), in early protection against infection with virulent Venezuelan equine encephalitis virus (VEE), we utilized mice with targeted mutations in the IFN-alpha/beta receptor, IRF-1, or IRF-2 genes. IFN-alpha/beta-receptor knockout mice are highly susceptible to peripheral infection with virulent or attenuated VEE, resulting in their death within 24 and 48 h, respectively. Treatment of normal macrophages with anti-IFN-alpha/beta antibody prior to and during infection with molecularly cloned virulent VEE resulted in increased VEE replication. However, treatment with high doses of IFN or IFN-inducing agents failed to alter percentage mortality or average survival times in mice challenged with a low dose of virulent VEE. In IRF-1 and IRF-2 knockout mice (IRF-1(-/-) and IRF-2(-/-)), the 100% protection against virulent VEE that is conferred by attenuated VEE within 24 h in control C57BL/6 mice was completely absent in IRF-2(-/-) mice, whereas 50% of IRF-1(-/-) mice were protected. IRF-2(-/-) mice were deficient in clearing VEE virus from the spleen and the brain compared to the heterozygous IRF-2(+/-) knockout or C57BL/6 (+/+) mice. Furthermore, a distinct pattern of histopathological changes was observed in brains of IRF-2(-/-) mice after VEE exposure. Taken together, these findings imply that the altered immune response in IRF-1 and IRF-2 knockout mice results in altered virus dissemination, altered virus clearance, and altered virus-induced pathology. Thus, type I Interferon, as well as IRF-1 and IRF-2, appears to play an important and necessary role in the pathogenesis of, and protection against, VEE infection.
John Hiscott - One of the best experts on this subject based on the ideXlab platform.
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differential regulation of human papillomavirus type 8 by Interferon Regulatory Factors 3 and 7
Journal of Virology, 2011Co-Authors: Rongtuan Lin, Monika Oldak, Liv Tolzmann, Artur Wnorowski, Marta Podgorska, Steffi Silling, John HiscottAbstract:The genus β human papillomavirus (HPV) type 8 is associated with nonmelanoma skin cancer in patients with epidermodysplasia verruciformis, and evidence for its protumorigenic potential in the general population increases. To date, strategies to suppress genus β HPV infections are limited. Interferon Regulatory Factors IRF-3 and IRF-7 play key roles in the activation of the innate immune response to viral infections. In this study, we show for the first time that both IRF-3 and IRF-7 regulate transcription of a papillomavirus, but with opposing effects. IRF-7, expressed in the suprabasal layers of human epidermis, increased HPV8 late promoter activity via direct binding to viral DNA. UV-B light-induced activation of the HPV8 promoter involved IRF-7 as a downstream effector. In contrast, IRF-3, expressed in all layers of human epidermis, induced strong HPV8 suppression in primary keratinocytes. IRF-3-mediated suppression prevailed over IRF-7-induced HPV8 transcription. Unlike the E6 oncoprotein of the mucosal high-risk HPV16, the HPV8 E6 protein did not bind to IRF-3 and only weakly antagonized its activity. Strong antiviral activity was also observed, when keratinocytes were treated with potent IRF-3 activators, poly(I:C) or RNA bearing 5′ phosphates. In conclusion, we show that IRF-3 activation induces a state of cell-autonomous immunity against HPV in primary human keratinocytes. Our study suggests that local application of IRF-3-activating compounds might constitute an attractive novel therapeutic strategy against HPV8-associated diseases, particularly in epidermodysplasia verruciformis patients.
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Differential regulation of human Interferon A gene expression by Interferon Regulatory Factors 3 and 7.
Molecular and Cellular Biology, 2009Co-Authors: Pierre Génin, John Hiscott, Ahmet CivasAbstract:Differential expression of the human Interferon A (IFN-A) gene cluster is modulated following paramyxovirus infection by the relative amounts of active Interferon Regulatory factor 3 (IRF-3) and IRF-7. IRF-3 expression activates predominantly IFN-A1 and IFN-B, while IRF-7 expression induces multiple IFN-A genes. IFN-A1 gene expression is dependent on three promoter proximal IRF elements (B, C, and D modules, located at positions −98 to −45 relative to the mRNA start site). IRF-3 binds the C module of IFN-A1, while other IFN-A gene promoters are responsive to the binding of IRF-7 to the B and D modules. Maximal expression of IFN-A1 is observed with complete occupancy of the three modules in the presence of IRF-7. Nucleotide substitutions in the C modules of other IFN-A genes disrupt IRF-3-mediated transcription, whereas a G/A substitution in the D modules enhances IRF7-mediated expression. IRF-3 exerts dual effects on IFN-A gene expression, as follows: a synergistic effect with IRF-7 on IFN-A1 expression and an inhibitory effect on other IFN-A gene promoters. Chromatin immunoprecipitation experiments reveal that transient binding of both IRF-3 and IRF-7, accompanied by CBP/p300 recruitment to the endogenous IFN-A gene promoters, is associated with transcriptional activation, whereas a biphasic recruitment of IRF-3 and CBP/p300 represses IFN-A gene expression. This Regulatory mechanism contributes to differential expression of IFN-A genes and may be critical for alpha Interferon production in different cell types by RIG-I-dependent signals, leading to innate antiviral immune responses.
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Interferon Regulatory Factors and the atypical ikk related kinases tbk1 and ikk e essential players in the innate immune response to rna virus infection
2009Co-Authors: Meztli Arguello, Suzanne Paz, John HiscottAbstract:This chapter opens with a brief overview of the toll-like receptor (TLR)-dependent and -independent pathways of activation. It then focuses on the activation of transcription Factors Interferon Regulatory Factors (IRFs) IRF3 and IRF7 by the atypical IκB kinases (IKKs), TANK-binding kinase 1 (TBK1), and IKK-e and their role in the induction of type I Interferons (IFNs). The majority of IRFs are involved in distinct aspects of the antiviral response, while two members—IRF4 and IRF8—function mainly as regulators of hematopoiesis in concert with the Ets transcription factor. Importantly, expression of the IKK-related kinases is essential to initiate IRF signaling in response to de novo Sendai virus (SeV), vesicular stomatitis virus (VSV), or measles virus infection, and treatment with RNA interference directed against either IKK-e or TBK1 reduces VSV-inducible IRF3 phosphorylation and IRF-dependent gene expression in human cells. Inhibition of Hsp90 expression by small interfering RNA (siRNA) resulted in an impaired activation of IRF3 following SeV infection. This study proposes that Hsp90 participates in the formation of a complex containing TBK1 and IRF3. In addition to linking TBK1 to the exocyst pathway and Ras-induced transformation, the study demonstrated that the host defense response requires the RalB/Sec5/TBK1 complex following double-stranded RNA (dsRNA) treatment or SeV infection.
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super activated Interferon Regulatory Factors can enhance plasmid immunization
Vaccine, 2003Co-Authors: Jonathan L Bramson, Rongtuan Lin, Kelley Dayball, Jennifer R Hall, James Millar, Mark Miller, Yonghong Wan, John HiscottAbstract:Abstract We have been investigating the adjuvant properties of two super-activated Interferon-Regulatory Factors (IRFs), IRF-3(5D) and IRF7/3A, identified in our previous studies of structure–function relationships, for enhancing plasmid vaccines. Intramuscular injection of plasmid cocktails encoding IRF-3(5D) and IRF7/3A molecules elicited cytotoxic T cell responses in over 80% of mice following a single immunization compared to a 20% response-rate using a control cocktail. Most interestingly, greater than 60% of mice immunized with the super-activated IRFs developed antigen-specific antibodies compared to 0% of the mice in the control group. Finally, vaccines which incorporated the super-activated IRFs provided greater protection against challenge with a recombinant vaccinia virus. These results support further investigation of the potential of these agents as adjuvants for genetic immunization.
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preferential binding sites for Interferon Regulatory Factors 3 and 7 involved in Interferon a gene transcription
Journal of Molecular Biology, 2002Co-Authors: Pierre Morin, John Hiscott, Rongtuan Lin, Jose Braganca, Marietherese Bandu, Janine Doly, Ahmet CivasAbstract:Transcription of the murine Interferon-A4 (IFN-A4) gene is mediated by a virus responsive element (VRE-A4) located in the promoter proximal [-120 to -43] region. VRE-A4 contains four DNA modules (A to D) which cooperate for maximal IFN-A4 activation following virus infection. The differential expression between the highly expressed IFN-A4 and the weakly inducible IFN-A11 gene promoters is essentially due to point mutations within the C and D modules of the virus-responsive element VRE-A11. We now demonstrate that in murine L929 and human 293 cells, transcription Factors IRF-3 and IRF-7, which are potent activators of virus-induced type I IFN transcription, differentially affect IFN-A4 and IFN-A11 promoter activities. Using electrophoretic mobility shift assays and DNase I footprinting data, our studies demonstrate that the AB modules correspond to a preferential site for IRF-7, whereas the C module is preferentially recognized by IRF-3. Furthermore, transfection of reporter constructs driven by four copies of different GAAANN hexameric motifs found within VRE-A4 indicates that the NN residues of these hexameric sequences define the preferential binding sites for IRF-3 or IRF-7. Together, these experiments clarify the molecular basis for differential expression of IFN-A genes following virus infection by delineating the sequence requirements for IRF association with the virus responsive elements of the IFN-A genes.
Tadatsugu Taniguchi - One of the best experts on this subject based on the ideXlab platform.
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regulation of cooperative function of the il12b enhancer and promoter by the Interferon Regulatory Factors 3 and 5
Biochemical and Biophysical Research Communications, 2013Co-Authors: Ryuji Koshiba, Hideyuki Yanai, Atsushi Matsuda, A Goto, Akira Nakajima, Hideo Negishi, Junko Nishio, Stephen T Smale, Tadatsugu TaniguchiAbstract:Abstract The regulation of the Il12b gene, encoding the shared p40 subcomponent for IL-12 and IL-23, is critical for innate immune responses and subsequent T cell polarization. This gene is robustly induced upon Toll-like receptor (TLR) stimulation, wherein an enhancer located 10 kb upstream of the transcription start site is required for promoter activity; however, the underlying mechanisms that regulate this enhancer in cooperation with the promoter has remained elusive. We show here that the Il12b enhancer contains functional ISREs for recognition by Interferon Regulatory Factors (IRFs), and provide evidence that TLR-activated IRF5 mediates cooperativity of the enhancer with the promoter which also contains ISREs. By contrast, IRF3 activated by cytosolic RIG-I-like receptor (RLR) signaling binds to these ISREs and causes gene suppression. Consistently, IRF5 binding is accompanied with chromatin remodeling of both Regulatory regions and the formation of a productive transcriptional complex containing other transcription Factors, whereas these events are inhibited by IRF3 binding. We show that the ISREs embedded in the enhancer are indeed critical for its activation by IRF5. We also adduce evidence that the 5′ sequences of the enhancer and promoter ISREs, all of which deviate from consensus ISREs, critically affect the function of IRF3. The dual commitment of these IRFs in the regulation of the Il12b enhancer and promoter is unique and may have implications for understanding the evolution of this gene.
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Regulation of immunity and oncogenesis by the IRF transcription factor family
Cancer Immunology Immunotherapy, 2010Co-Authors: David Savitsky, Hideyuki Yanai, Tomohiko Tamura, Tadatsugu TaniguchiAbstract:Nine Interferon Regulatory Factors (IRFs) compose a family of transcription Factors in mammals. Although this family was originally identified in the context of the type I Interferon system, subsequent studies have revealed much broader functions performed by IRF members in host defense. In this review, we provide an update on the current knowledge of their roles in immune responses, immune cell development, and regulation of oncogenesis.
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Interferon Regulatory factor family of transcription Factors and regulation of oncogenesis
Cancer science, 2008Co-Authors: Akinori Takaoka, Tomohiko Tamura, Tadatsugu TaniguchiAbstract:A family of transcription Factors, the Interferon Regulatory Factors (IRF), was identified originally in the context of the regulation of the type I Interferon (IFN)-α/β system. The IRF family has now expanded to nine members, and gene-disruption studies have revealed the critical involvement of these members in multiple facets of host defense systems, such as innate and adaptive immune responses and tumor suppression. In the present review article, we aim at summarizing our current knowledge of the roles of IRF in host defense, with special emphasis on their involvement in the regulation of oncogenesis. (Cancer Sci 2008; 99: 467–478)
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type i inteferon gene induction by the Interferon Regulatory factor family of transcription Factors
Immunity, 2006Co-Authors: Kenya Honda, Akinori Takaoka, Tadatsugu TaniguchiAbstract:Summary Induction of type I Interferons (IFNs) by viruses and other pathogens is crucial for innate immunity, and it is mediated by the activation of pattern-recognition receptors, such as Toll-like receptors and cytosolic receptors such as RIG-I and MDA5. The type I IFN induction is primarily controlled at the gene transcriptional level, wherein a family of transcription Factors, Interferon Regulatory Factors (IRFs), plays central roles. Here, we summarize the recent studies on IRFs, providing a paradigm of how genes are ingeniously regulated during immune responses. We also consider some evolutional aspects on the IFN-IRF system.
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The Interferon Regulatory Factors and oncogenesis.
Seminars in cancer biology, 2000Co-Authors: Nobuyuki Tanaka, Tadatsugu TaniguchiAbstract:Abstract We study a family of transcription Factors, the Interferon Regulatory Factors (IRFs), as originally identified in the context of the regulation of type-I Interferon (IFN- α / β ) system. Most notably, studies on IRF-1 have revealed its remarkable functional diversity in the regulation of cellular responses of host defense, including oncogenesis. The IRF family has now expanded to nine members, and gene disruption studies have revealed critical involvement of some of the members in the regulation of cell growth and oncogenesis. In this review, we summarize our current knowledge on the involvement of members of the IRF family members, in particular, IRF-1, in oncogenesis.
Paula M. Pitha - One of the best experts on this subject based on the ideXlab platform.
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distinct roles of kaposi s sarcoma associated herpesvirus encoded viral Interferon Regulatory Factors in inflammatory response and cancer
Journal of Virology, 2013Co-Authors: Petra Baresova, Paula M. Pitha, Barbora LubyovaAbstract:Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). Similar to other herpesviruses, KSHV has two life cycles, latency and lytic replication. In latency, the KSHV genome persists as a circular episome in the nucleus of the host cell and only a few viral genes are expressed. In this review, we focus on oncogenic, antiapoptotic, and immunomodulating properties of KSHV-encoded homologues of cellular Interferon Regulatory Factors (IRFs)--viral IRF1 (vIRF1) to vIRF4--and their possible role in the KSHV-mediated antiviral response, apoptosis, and oncogenicity.
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regulation of dna raised immune responses by cotransfected Interferon Regulatory Factors
Journal of Virology, 2002Co-Authors: Shin Sasaki, Paula M. Pitha, Rama Rao Amara, Wenshuz Yeow, Harriet L RobinsonAbstract:Interferon Regulatory factor 1 (IRF-1), IRF-3, and IRF-7 have been tested as genetic adjuvants for influenza virus hemagglutinin (HA) and nucleoprotein vaccine DNAs. Cotransfection of HA with IRF-3 and IRF-7 increased CD4 T-cell responses by 2- to 4-fold and CD8 T-cell responses by more than 10-fold. Following intramuscular deliveries of DNA, both CD4 and CD8 T cells were biased towards type 1 immune responses and the production of gamma Interferon. Following gene gun bombardments of DNA, both were biased towards type 2 immune responses and the production of interleukin-4. The biases of the T-cell responses towards type 1 or type 2 were stronger for immunizations with IRF-3 as an adjuvant than for immunizations with IRF-7 as an adjuvant. Moderate adjuvant effects for antibody were observed. The isotypes of the antibody responses reflected the method of DNA delivery; intramuscular deliveries of DNA predominantly raised immunoglobulin G2a (IgG2a), whereas gene gun deliveries of DNA predominantly raised IgG1. These biases were enhanced by the codelivered IRFs. Overall, under the conditions of our experiments, IRF-3 had good activity for T cells, IRF-7 had good activity for both antibody and T cells, and IRF-1 had good activity for antibody.
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Interferon Regulatory Factors bridging antiviral defense growth control and immunoregulation
Journal of Interferon and Cytokine Research, 2002Co-Authors: John Hiscott, Paula M. PithaAbstract:3 SINCE THEIR DISCOVERY IN 1957, Interferons (IFN) have continuously played a central role in basic, applied, and clinical research as mediators of antiviral and antigrowth responses, as modulators of the immune response, and as therapeutic agents to combat viral diseases and cancer. IFN have served also as an important paradigm to investigate cytokine responses, signal transduction, and transcription control. Much of the information available on IFN gene regulation has derived from studies on the family of type I IFN genes, as well as the IFNstimulated genes (ISG), and has resulted in characterization of novel transcriptional proteins, common and unique signalling pathways leading to IFN and ISG activation, and the discovery of the IFN Regulatory Factors (IRF) and signal transducers and activators of transcription (Stat) families. IRF-1 and IRF-2 were originally identified as the transcriptional activator and repressor, respectively, of the type I IFN genes. The family has now expanded to include seven additional members: IRF-3 IRF-4 (Pip/LSIRF/ICSAT), IRF-5, IRF-6, IRF-7, IRF-8 (IFN consensus sequence binding protein [ICSBP]), and IRF-9 (ISG factor 3g/p48 [ISGF3g/p48]), and with the expansion has come the recognition of essential roles of IRF in immune regulation, growth control, and hematopoietic differentiation. All IRF share a high degree of homology in the N-terminal DNA binding domain and generally bind the DNA sequence GAAANNGAAANN. Variations in this canonical sequence, together with IRF interactions with other transcriptional partners, lead to the generation of transactivation and in some cases transrepression potential. Additional mechanisms allowing for differential gene regulation by IRF include cell type specificity, subcellular localization, and activator-specific phosphorylation events. The C-terminal portion of the IRF proteins is unique to each member and also contributes to the functional diversification of the IRF. The presence of virally encoded versions of IRF (vIRF) in the genome of human herpesvirus-8 (HHV-8), the virus responsible for Kaposi’s sarcoma, also illustrates the fact that viruses have evolved numerous mechanisms to evade the antiviral effect of IFN, including strategies to target the IRF. This Special Issue of the Journal of Interferon and Cytokine Research brings together many of the world’s leading researchers on this subject, and together they provide a comprehensive view of the range of activities controlled by the IRF family members. B. Barnes and colleagues provide an overview of the functions of the IRF in the innate immune response and immune evasive tactics of the vIRF homologs. Hauser’s group and Romeo’s group discuss the antiproliferative and tumorsuppressive properties of IRF-1. A. Battistini and colleagues describe the role of IRF-1 in regulating transcription from the HIV-1 long terminal repeat, and R. Pine illustrates a role for the IRF in the host response to mycobacterial infection. IRF-3 and IRF-7 are specifically involved in type I IFN gene expression. Viral infection causes the activation of an unknown kinase(s) and phosphorylation of both IRF-3 and IRF-7 in the cytoplasm. Virus-activated IRF-3/IRF-7 may undergo a conformational change that allows specific DNA binding to the type I IFN promoters, coactivator recruitment, and transcription of target genes. Several reviews cover this active area of research. M. Servant and colleagues discuss the structure and functional activation of IRF-3 and IRF-7. Fujita’s group provides a view of the Regulatory phosphorylation events responsible for IRF-3 induction, and N.C. Reich reviews her studies on the mechanisms of nuclear import and export of IRF-3. Structure-function studies on the related IRF-7 factor are described by D. Levy and colleagues; L. Zhang and J.S. Pagano contribute a distinct view of IRF-7 from the perspective of the involvement of IRF-7 in control of Epstein-Barr virus transcription. A. Civas’s group describes the interactions of IRF-3 and IRF-7 with the IFN-a promoters. The lymphoid-myeloid-restricted members of the IRF family are also reviewed. S. Marecki and M. Fenton analyze the structure and function of IRF-4, with emphasis on the role of IRF-4 in macrophage-specific gene regulation, and A. Pernis addresses the functions of IRF-4 in T and B lymphoid cellspecific gene expression. From a different viewpoint, Y. Mamane and colleagues focus on the consequences of IRF-4 constitutive activation in human T cell leukemia virus (HTLV-1)infected lymphoid cells. T. Tamura and K. Ozato review their studies on the role of IRF-8/ICSBP in myeloid differentiation and the regulation of myeloid-specific target genes by IRF-8. B.-Z. Levi and colleagues review the functional protein-protein
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recruitment of multiple Interferon Regulatory Factors and histone acetyltransferase to the transcriptionally active Interferon a promoters
Journal of Biological Chemistry, 2001Co-Authors: Paula M. PithaAbstract:Abstract Type I Interferon (IFN) plays a critical role in the innate immunity against viral infection. Expression of IFNA genes in infected cells is cell type-dependent and is regulated at the transcriptional level. The present study is focused on the molecular mechanism underlying the differential expression of human IFNA1 and A2 genes. Two nucleotides, at positions −98 and −81 of IFNA1 and A2 promoter, were pivotal to the differential expression. The DNA pull-down and chromatin precipitation assays have shown that nuclear Interferon Regulatory factor (IRF)-3 and IRF-7 as well as IRF-1 bind to IFNA1 virus-responsive element (VRE). Interestingly, overexpression of IRF-7 increased the otherwise weak binding of both IRF-3 and IRF-7 to IFNA2 VRE. These data together with the results of two-step chromatin immunoprecipitation strongly suggest that the IRF-3 and IRF-7 bind to IFNA1 promoter as a dimer. Furthermore, binding of IRF-3 and IRF-7 to IFNA VRE is associated with the presence of acetylated histone H3, suggesting that histone acetyltransferase(s) is tethered together with virus-activated IRF-3 and IRF-7 to the IFNA1 promoter. In addition, the constitutively active IRF-3 (5D) and IRF-7 (2D) mutants activate the endogenous IFNA genes in uninfected cells; however, the expression profile of IFNA is not identical to that induced by viral infection.
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role of the Interferon Regulatory Factors irfs in virus mediated signaling and regulation of cell growth
Biochimie, 1998Co-Authors: Paula M. Pitha, John Hiscott, William J Lowther, Yuangt Juang, Susan L Schafer, Ladislaw Burysek, Paul A MooreAbstract:Abstract As a response to viral infection, cells express the early inflammatory genes that encode small proteins generally called cytokines or chemokines. These protein can activate immune responses to viral infection as well as to modulate directly the outcome of viral infection. The group of proteins with the direct antiviral effects have been called Interferons. The stimulation of Interferon synthesis in infected cells is regulated on a transcriptional level and two families of cellular transcriptional Factors seem to play a critical role in the transcriptional activation of Interferon genes. The first one are the proteins of NF-κB family and the second is the family of the Interferon responsive Factors. While both of the types of the transcriptional Factors are important for the induction of Interferon beta gene, the NF-κB factor do not seems to participate in the induction of Interferon alpha genes. The present review is focused on the recently identified new members of cellular IRF family and their role in virus mediated response, responses and cell growth. In addition the HHV-8 encoded vIRFs are described.
Natalia Cuesta - One of the best experts on this subject based on the ideXlab platform.
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transcriptional regulation of lipopolysaccharide lps induced toll like receptor tlr expression in murine macrophages role of Interferon Regulatory Factors 1 irf 1 and 2 irf 2
Journal of Endotoxin Research, 2006Co-Authors: Natalia Cuesta, Stefanie N VogelAbstract:Activation of TLRs is most closely associated with induction of pro-inflammatory gene expression; however, expression of many other genes, including the TLR genes themselves, has also been shown to be modulated following TLR engagement. A large family of nuclear transcription Factors, the Interferon Regulatory Factors (IRFs), have been implicated in TLR signaling leading to pro-inflammatory gene expression. Given that IRF-1 and IRF-2 counter-regulate the transcriptional activity of many genes, we hypothesized that IRF-1 and IRF-2 might also regulate TLR gene expression following LPS stimulation of murine macrophages. mRNA derived from medium- or LPS-treated primary peritoneal macrophages was analyzed for TLR gene expression using quantitative real-time PCR. In wild-type macrophages, LPS up-regulated expression of TLRs 1—3 and 6—9 steady-state mRNA, while TLR4 mRNA was modestly downregulated. IRF-2—/ — macrophages responded to LPS with dysregulated expression of TLR3, TLR4, and TLR5 mRNA, whereas IRF-1 def...
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transcriptional regulation of lipopolysaccharide lps induced toll like receptor tlr expression in murine macrophages role of Interferon Regulatory Factors 1 irf 1 and 2 irf 2
Journal of Endotoxin Research, 2006Co-Authors: Quan M Nhu, Natalia Cuesta, Stefanie N VogelAbstract:Activation of TLRs is most closely associated with induction of pro-inflammatory gene expression; however, expression of many other genes, including the TLR genes themselves, has also been shown to be modulated following TLR engagement. A large family of nuclear transcription Factors, the Interferon Regulatory Factors (IRFs), have been implicated in TLR signaling leading to pro-inflammatory gene expression. Given that IRF-1 and IRF-2 counter-regulate the transcriptional activity of many genes, we hypothesized that IRF-1 and IRF-2 might also regulate TLR gene expression following LPS stimulation of murine macrophages. mRNA derived from medium- or LPS-treated primary peritoneal macrophages was analyzed for TLR gene expression using quantitative real-time PCR. In wild-type macrophages, LPS up-regulated expression of TLRs 1-3 and 6-9 steady-state mRNA, while TLR4 mRNA was modestly down-regulated. IRF-2(-/-) macrophages responded to LPS with dysregulated expression of TLR3, TLR4, and TLR5 mRNA, whereas IRF-1 deficiency dampened LPS-induced mRNA expression for TLR3, TLR6, and TLR9. Functional studies revealed aberrant TLR3 signaling in IRF-2(-/-) macrophages. Collectively, these findings reveal an additional level of complexity associated with TLR transcriptional regulation and suggest that the trans-acting Factors, IRF-1 and IRF-2, contribute to the innate immune response to infections by regulating TLR gene expression.