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Results for “Interferon Regulatory Factor-1”

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At least 19 recordsLinked to original sources
PubMed1992

Interferon regulatory factor-1 (IRF-1) activates the synthetic IRF-1-responsive sequence (GAAAGT)4 in Saccharomyces cerevisiae.

In appropriate mammalian cells, interferon regulatory factor-1 (IRF-1) can activate the virus-responsive element of the IFN-beta promoter (VRE beta") or the synthetic oligonucleotide (GAAAGT)4. The latter contains two copies of the functional equivalent of PRDI, one of the regulatory domains of VRE beta". We prepared yeast strains containing an IRF-1 expression plasmid under the control of the galactose-inducible Gal1 promoter and a reporter plasmid with either (GAAAGT)4, VRE beta", or other test sequences placed upstream of a minimal promoter linked to the beta-galactosidase coding sequence. Upon induction of IRF-1 expression, the (GAAAGT)4-containing promoter was activated, but VRE beta" and all other sequences tested were inactive. Our results showed that IRF-1 belongs to a class of higher eukaryotic transcription factors that can interact with the yeast transcriptional machinery. Our findings also raised the question why the duplicate PRDI-like sequences in (GAAAGT)4 can be activated by IRF-1 synthesized in yeast, but not VRE beta", which also contains at least two PRDI-like sequences.

Base Sequence↗
PubMed1992

Interferon regulatory factor-1 is inducible by prolactin, interleukin-2 and concanavalin A in T cells.

Interferon regulatory factor-1 (IRF-1) gene expression is rapidly upregulated in the prolactin (PRL)-activated Nb2 rat T lymphoma cell line. To further elucidate its role as a T cell activation molecule, IRF-1 gene expression in response to various T cell stimuli was examined. In Nb2 T cells, PRL induced two peaks of IRF-1 gene expression: a rapid, transient peak at 1 h and a sustained peak at 12 h. PRL subsequently induced interferon-gamma (IFN-gamma) gene expression at 3-6 h. However, the early induction of IRF-1 and IFN-gamma does not appear to be interdependent. Interleukin-2 (IL-2) also induced IRF-1 gene expression in Nb2 T cells but only one broad peak at 10 h was observed. In primary mouse splenocytes, concanavalin A induced rapid and transient expression of the IRF-1 gene; maximal expression occurred by 6 h, and then returned to basal levels by 12-15 h. These results provide additional evidence for the importance of IRF-1 in T cell activation.

Animals↗
PubMed1992

The activation of major histocompatibility complex class I genes by interferon regulatory factor-1 (IRF-1).

We have investigated the role of interferon regulatory factor-1 (IRF-1), an interferon-gamma (IFN-gamma) inducible transcriptional activator, on major histocompatibility complex (MHC) class I gene transcription. IRF-1 alone is sufficient to trans-activate both transfected and endogenous class I genes and the effect of IRF-1 appears to be direct and sequence-specific. These data suggest that IRF-1 is involved in the IFN-gamma mediated induction of MHC class I expression.

Base Sequence↗
PubMed1992

The transcription factor interferon regulatory factor-1 is expressed during both early G1 and the G1/S transition in the prolactin-induced lymphocyte cell cycle.

PRL induces quiescent Nb2 rat T-lymphoma cells to undergo mitogenesis. Upon PRL stimulation, the transcription factor interferon regulatory factor-1 (IRF-1) is induced as a novel T-cell activation gene in Nb2 cells. Surprisingly, IRF-1 is expressed twice during a single PRL-induced growth cycle: first during the early G1 phase, in an immediate transient peak from 15 min to 2 h, and second during the G1/S phase transition, in a broader peak beginning at 8 h. The unusual biphasic expression of IRF-1 mRNA is accompanied both times by de novo IRF-1 protein synthesis. However, the rate of IRF-1 protein turnover appears to be different in G1 and S phases. IRF-1 protein expressed in G1 exhibits a half-life of about 25 min, whereas in the S phase, the half-life is about 60 min. By washing out PRL at various times during G1, we found a direct correlation among the length of PRL exposure, the second peak of IRF-1 mRNA expression, and DNA synthesis. Our data suggest that PRL and one putative nuclear mediator, IRF-1, may be important in two distinct phases of the cell cycle: first in cell cycle activation, and then in S phase progression.

Animals↗
PubMed1992

Double-stranded RNA and interferon-alpha induce transcription through different molecular mechanisms.

Double-stranded (ds) RNA stimulates the synthesis of several mRNAs known to be induced by type I interferons (IFNs). In this report, it is shown that the IFN-alpha stimulated genes (ISGs) 15, 54, 56, and GBP are transcriptionally induced by dsRNA. Transcriptional stimulation occurred in the presence of the protein synthesis inhibitor cycloheximide (CHX), indicating that inducibility was directly mediated by dsRNA through the action of preformed proteins. ISGF-3, the protein complex mediating primary transcriptional induction of ISGs by IFN-alpha, was not activated by dsRNA in the presence of CHX. Additionally, DNA-binding activity of ISGF-2/IRF-1, a protein involved in the regulation of the IFN-beta gene and ISGs, did not correlate with dsRNA-induced transcriptional induction of ISGs. This suggests that dsRNA and IFN-alpha induce ISGs through different molecular mechanisms.

Cycloheximide↗
PubMed1992

Identification of novel factors that bind to the PRD I region of the human beta-interferon promoter.

Treatment of cells with virus or synthetic double-stranded RNA (dsRNA) leads to the transient transcriptional activation of the beta-interferon gene. Genetic analysis has revealed that the 5' regulatory sequence responsible for this induction contains multiple positive and negative elements. One of these, Positive Regulatory Domain I (PRD I), has been shown to bind the positively-acting transcription factor IRF-1. In this study we show that this element is inducible under conditions where IRF-1 cannot be detected, suggesting that additional cellular factors are involved in the induction process. To investigate the existence of such factors we have analysed the range and properties of PRD I-binding activities present in HeLa cells. In addition to the repressor protein IRF-2, several novel factors can bind to PRD I in uninduced cells: two of these have properties consistent with a role in negative regulation; levels of two others increase upon priming, and may be alternative candidates for activators. Upon induction we also observe a novel factor whose appearance does not depend upon de novo protein synthesis, and which appears to be a truncated form of IRF-2. The potential involvement of these factors in regulating the beta-interferon gene is discussed.

Base Sequence↗
PubMed1992

[Function, molecular structure and gene expression of interferons].

Interferon is a key substance of the cytokine network, and is functioning not only as the virus inhibitory factor, but also as the factor for differentiation, development, and homeostasis of animals, including man. The molecular structure, induction mechanisms, interaction with receptor, and antiviral action mechanisms of IFN were reviewed. 1. Molecular structure of IFN IFNs are now divided into 4 types--alpha, beta, gamma, omega--according to antigenicities of IFN proteins, and to base sequence of their genes. The omega type was established officially on 1990 by the Nomenclature Committee of International Society for Interferon Research (ISIR). Also, the genes for HuIFNs were named as follows; HuIFN-A for HuIFN-alpha, HuIFN-B for HuIFN-beta, HuIFN-G for HuIFN-gamma, and HuIFN-W for HuIFN-omega. Nevertheless, the names of Type I IFN and Type II IFN are still valuable, since members of Type I IFN, alpha, beta, and omega, are similar in their molecular structures, and they share the common receptor (Type I IFN receptor), on the other hand, HuIFN-gamma (the only one member of Type II IFN) has different characteristics from the other IFNs, and binds to its specific receptor (Type II IFN receptor). However, it has been reported that both N-terminal and C-terminal of IFN protein of all types, participate in the binding of IFN to its receptor. 2. Induction mechanism of IFN. The factors, IRF-1 and IRF-2, were found to play an important role in IFN induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Requirement for prolactin during cell cycle regulated gene expression in cloned T-lymphocytes.

The neuroendocrine hormone PRL acts as a progression factor during interleukin-2 (IL2) stimulated lymphocyte proliferation. Since the sequential expression of cell cycle regulated genes occurs during this process, we examined the contribution of IL2 and PRL to specific RNA accumulation. Stimulation of the cloned T cell line L2 with IL2 and PRL induced the sequential expression of interferon regulatory factor-1, c-myc, proliferating cell nuclear antigen, thymidine kinase, cyclin B, and histone H3. Stimulation of L2 cells with PRL alone, however, induced only the expression of interferon regulatory factor-1. Depletion of PRL, through the use of an anti-PRL antiserum, inhibited IL2 driven proliferation and the expression of cyclin B and histone H3. These results demonstrate that PRL may regulate T cell proliferation by enhancing the expression of some genes necessary for entry into S-phase.

Animals↗
PubMed1992

Critical role of a common transcription factor, IRF-1, in the regulation of IFN-beta and IFN-inducible genes.

Interferon regulatory factor 1 (IRF-1) is a protein that binds to cis-elements within the promoter of interferon (IFN)-beta and some IFN-inducible genes. We used a human fibroblast line, GM-637, to generate stable transfectants constitutively expressing IRF-1 mRNA in either the sense or antisense orientation. Upon induction with poly-(I).poly(C) or Newcastle disease virus, cells expressing sense IRF-1 mRNA produced significantly higher levels of IFN-beta mRNA and protein than control cells, whereas cells expressing antisense IRF-1 mRNA produced little or no IFN-beta mRNA and protein. Furthermore, clear differences were seen among the transfectants in the level of expression of two IFN-induced genes (2'-5'-oligoadenylate synthetase and class I HLA). Our data show that IRF-1 is essential for the induced expression of the IFN-beta gene. The results also indicate an important role of IRF-1 in the expression of IFN-inducible genes and suggest a role for IRF-1 in many other cytokine actions.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Human interferon regulatory factor 1: intron-exon organization.

Interferon (IFN) regulatory factor 1 (IRF-1) is a transcriptional regulatory protein that mediates the transcriptional activation of the IFN-alpha and IFN-beta genes by viruses and IFNs. To characterize the mechanisms that govern the level of IRF-1 in cells, we isolated the IRF-1 gene and characterized the structure of its intronic and exonic domains and of its regulatory promoter region. A human placental genomic library was screened with an IRF-1 cDNA probe, and two clones that contained the IRF-1 gene and its 5' regulatory region were obtained. We used these clones to determine the complete nucleotide sequence for the IRF-1 gene, finding that the IRF-1 gene spanned 7.72 kb of DNA and included 10 exons and 9 introns. When the deduced amino acid sequences were compared among different species, the most conserved exons were exons 2, 3, and 4, in which the putative DNA binding domain for the IRF-1 protein is located.

Amino Acid Sequence↗
PubMed1992

Constitutive expression of an ISGF2/IRF1 transgene leads to interferon-independent activation of interferon-inducible genes and resistance to virus infection.

Interferon (IFN)-stimulated gene factor 2 (ISGF2) plays a role in transcription of the beta IFN (IFN-beta) gene and IFN-stimulated genes (ISGs) and may function as a central mediator of cytokine responses. Constitutive ISGF2 transgene expression resulted in substantial resistance to three RNA virus families. This phenotype was not a consequence of IFN production and may have arisen directly through ISG expression. ISGF2 acted generally as a positive transcription factor through binding sites from several genes, in the context of transient cotransfection. Constitutive transcription of the endogenous IFN-beta gene, and several genes that are normally induced by either IFN-alpha or IFN-gamma, or only by IFN-alpha, was elevated in cells that constitutively express an ISGF2 transgene. However, constitutive and virus-induced levels of IFN-beta mRNA were unaffected in such cell lines.

Antibodies, Viral↗
PubMed1992

Increased levels of interferon regulatory element-binding activities in nuclei of high interferon-producing If-1h mice.

The transient induction of type I interferon (IFN) genes following a viral infection involves transcriptional derepression and activation, mediated by positive and negative factors which bind to upstream cis-acting elements. We have transfected the human IFN-beta gene into primary splenocytes from mice regulated by the If-1 locus and have shown that the exogenous gene is regulated by this locus in a manner similar to that of endogenous IFN genes. Using nuclear extracts from splenocytes of C57BL/6 (If-1h) and BALB/c (If-1l) mice in gel retardation assays, we found that levels of DNA-binding activities for the interferon regulatory element and its subelements were constitutive in nuclear extracts of spleen cells. Levels of DNA binding to the interferon regulatory element were higher in extracts from the nuclei of If-1h mice and thus correlate with the higher levels of human IFN-beta mRNA detected in these transfected cells and the transcription of the endogenous IFN genes. Higher levels of DNA-binding/transcription factors found in nuclei from spleen cells of If-1h mice may be involved in the expression of the If-1 phenotype.

Animals↗
PubMed1992

Differential response of human interferon-beta promoter elements to trans-activation by HSV VP16 and IRF-1.

The trans-activation potential of herpes simplex virus (HSV) VP16, either alone or in combination with interferon regulatory factor 1 (IRF-1), was examined using hybrid promoters containing different regulatory elements from the interferon-beta promoter. Coexpression of HSV VP16 and IRF-1 differentially activated the AAGTGA hexamer construct Th(2), the AAAGGA hexamer Thm(2) construct, and the natural IFN-beta promoter. Surprisingly, high concentrations of IRF-1 inhibited expression of the PRDII containing reporter P2(1)/CAT. These results indicate that trans-activation by HSV VP16, acting through distinct cellular transcription factors, may be involved in stimulation of IFN-beta regulatory domains.

DNA-Binding Proteins↗
PubMed1992

Identification of a functionally important sequence in the C terminus of the interferon-gamma receptor.

We have previously shown that the intracellular domain of the interferon-gamma (IFN-gamma) receptor plays an obligate role in receptor-mediated signal transduction. Moreover, we have specifically identified two regions within the human IFN-gamma receptor's intracellular domain required for functional activity: the membrane-proximal 48 amino acids required for both functional activity and receptor-mediated ligand internalization and the C-terminal 39 amino acids required exclusively for biologic response induction. Herein we report the identification of the 3 amino acids within the C-terminal region of the receptor that are obligatorily required for receptor function. By using a set of overlapping truncation mutants, the minimal functional sequence within the C-terminal region was localized to residues 434-444 (APTSFGYD-KPH). By mutating each individual residue within this sequence to alanine, three residues (Tyr-440, Asp-441, and His-444) were identified as being critical for IFN-gamma-dependent (i) upregulation of major histocompatibility complex class I proteins, (ii) activation of the IFN regulatory factor 1 gene, and (iii) stimulation of cells to produce nitric oxide. The more conservative Tyr-440-->Phe substitution also resulted in a nonfunctional receptor. Subsequent mutational analysis of all five of the IFN-gamma receptor's intracellular tyrosine residues revealed that Tyr-440 was the sole tyrosine required for receptor activity. These results thus identify a unique sequence in the IFN-gamma receptor that is required for initiation of IFN-gamma-dependent biologic responses and highlight the importance of the hydroxyl side chain of Tyr-440 in this process.

Amino Acid Sequence↗
PubMed2025

Rare epigenetic alterations are conserved across hematopoietic differentiation stages after mycobacterial infection.

Infection leads to durable cell-autonomous changes in hematopoietic stem and progenitor cells (HSPCs), resulting in production of innate immune cells with heightened immunity. The mechanisms underlying this phenomenon, termed central trained immunity, remain poorly understood. We hypothesized that infection induces histone modifications leading to changes in chromatin accessibility that are conserved during differentiation from HSPCs to myeloid progenitors and monocytes. We conducted genome-wide surveillance of histone marks H3K27ac and H3K4me3 and chromatin accessibility in hematopoietic stem cells, multipotent progenitor 3, granulocyte-monocyte progenitors, and monocytes and macrophages of naive and Mycobacterium avium-infected mice. IFN signaling pathways and related transcription factor binding motifs including IRFs, NF-κB, and CEBP showed increased activating histone marks and chromatin accessibility across cell types. However, histone marks and increased chromatin accessibility were conserved at only a few loci, notably Irf1 and Gbp6. Knock out of IRF1 disrupted enhanced mitochondrial respiration and bacterial killing in human monocyte cell lines, while GBP6-KO monocyte cell lines showed dysregulated mitochondrial respiration. In summary, this study identifies IRF1 and GBP6 as 2 key loci at which infection-induced systemic inflammation leads to epigenetic changes that are conserved from HSPCs to downstream monocytes, providing a mechanistic avenue for central trained immunity.

Animals↗
PubMed2026

IL1B-centered immune dysregulation involving IL7R, CCR7, ITGB2 and IRF1 across insomnia and inflammatory bowel disease.

BACKGROUND: Insomnia is a prevalent sleep disorder that strongly affects one's quality of life and physical well-being. Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestines, and a majority of IBD patients suffer from comorbid insomnia. However, the shared molecular features linking insomnia and IBD remain poorly characterized. METHODS: Common differentially expressed genes (DEGs) were identified in datasets of insomnia (GSE208668) and IBD (GSE179285) using the Limma package. Functional enrichment was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Protein-protein interaction (PPI) network construction and hub gene identification was subsequently performed. Furthermore, we validated the reliability of the hub genes using qRT-PCR and Enzyme-linked immunosorbent assay (ELISA). In addition, we constructed a TF-miRNA regulatory network of hub genes and assessed the abundance of immune cell infiltration in insomnia and IBD using CIBERSORT, EPIC, and xCell algorithms. Finally, we utilized the DsigDB to predict potential therapeutic candidates. RESULTS: The analysis revealed 75 upregulated and 32 downregulated common DEGs. Functional enrichment analysis revealed the inflammatory response and immune activation as pivotal drivers underlying the pathogenesis of both insomnia and IBD. Five hub DEGs, namely, IL1B, IL7R, CCR7, ITGB2, and IRF1, were subsequently screened and validated. The TF-miRNA-mRNA regulatory network consisted of 5 TFs, 14 miRNA nodes and 5 core mRNA nodes. Immune cell infiltration analysis revealed several patterns shared between insomnia and IBD. Additionally, 10 potential therapeutic drugs for insomnia and IBD were proposed. CONCLUSION: Integrative coexpression network analysis reveals convergent dysregulation of an IL1B-centered immune module (comprising IL7R, CCR7, ITGB2, and IRF1) across insomnia and IBD, a shared immune disturbance and candidate targets for simultaneous intervention upon further mechanistic validation.

Humans↗