Frontline: Interferon regulatory factor-1 as a protective gene in intestinal inflammation: role of TCRγ δ T cells and interleukin-18-binding protein

2004 ◽  
Vol 34 (9) ◽  
pp. 2356-2364 ◽  
Author(s):  
Britta Siegmund ◽  
Joseph A. Sennello ◽  
Hans A. Lehr ◽  
Giorgio Senaldi ◽  
Charles A. Dinarello ◽  
...  
Keyword(s):  
T Cells ◽  
Intestinal Inflammation ◽  
Binding Protein ◽  
Interferon Regulatory Factor ◽  
Interleukin 18 ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
Protective Gene

The Pivotal Role of Signal Regulatory Protein α in Exacerbating Pulmonary Fibrosis Complicated with Bacterial Infection

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yamaguchi R ◽  
◽  
Sakamoto A ◽  
Haraguchi M ◽  
Narahara S ◽  
...  
Keyword(s):  
Immune Response ◽  
Pulmonary Fibrosis ◽  
Bacterial Infection ◽  
Signaling Pathway ◽  
Regulatory Protein ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
Th1 Immune Response

The pathogenesis of pulmonary fibrosis remains unknown. However, bacterial infections in patients with idiopathic pulmonary fibrosis are a serious complication that exacerbate the disease. Serum levels of Surfactant Protein D (SPD) are known to be elevated in patients with pulmonary fibrosis, but the role of SPD in pulmonary fibrosis complicated with bacterial infection is unknown. Lipopolysaccharide upregulates Interleukin (IL)-12p40 expression and IL-12p40 promotes Interferon Gamma (IFNγ) production to induce the T helper cell 1 (Th1) immune response via Signal Transducers and Activators of Transcription 4 (STAT4) signaling. A lack of IFNγ shifts the immune response from Th1 to Th2. IL-4 is a profibrotic Th2 cytokine that activates fibroblasts. Granulocyte-macrophage colony-stimulating factor induced by IL-1 and TNFα during the Th1 immune response upregulates Signal Regulatory Protein α (SIRPα) expression. Interferon Regulatory Factor 1 (IRF1) functions as the promoter activator of IL-12p40 after stimulation with LPS. SPD is a ligand for SIRPα, and SPD/SIRPα ligation activates the Mitogen-Activated Protein Kinase (MAPK)/Extracellular Signal-Related Kinase (ERK) signal cascade; ERK downregulates Interferon Regulatory Factor 1 (IRF1) expression. Consequently, the SPD/SIRPα signaling pathway decreases IL-12p40 production in human macrophages after exposure to LPS. IL-12p40 is a key immunoregulatory factor in bacterial infection that promotes production of IFNγ by T lymphocytes. Pulmonary fibroblasts are activated by IL-4/IL-4R ligation. IFNγ induces IRF1 via STAT1 signaling, and IRF1 acts as the promoter repressor of IL-4 to attenuate its production. IFNγ also inhibits IL-4R expression. A reduction in IFNγ induced by IL-12p40 deficiency via the SPD/SIRPα signaling pathway enhances IL-4 and IL-4R expression to augment the activity of fibroblasts. This finding indicates that pulmonary fibrosis is exacerbated by SPD/SIRPα signaling during bacterial infection.

scholarly journals A RUNX3 enhancer polymorphism associated with ankylosing spondylitis influences recruitment of Interferon Regulatory Factor 5 and factors of the Nucleosome Remodelling Deacetylase Complex in CD8+ T-cells

2019 ◽  
Author(s):  
Matteo Vecellio ◽  
Adrian Cortes ◽  
Sarah Bonham ◽  
Carlo Selmi ◽  
Julian C Knight ◽  
...  
Keyword(s):  
T Cells ◽  
Ankylosing Spondylitis ◽  
Cd8 T Cells ◽  
Binding Protein ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Nurd Complex ◽  
Nucleosome Remodeling ◽  
Nuclear Extracts ◽  
Functional Consequences

ABSTRACTObjectivesTo investigate the functional consequences of the single nucleotide polymorphism rs4648889 in a putative enhancer upstream of the RUNX3 promoter strongly associated with ankylosing spondylitis (AS).MethodsThe effects of rs4648889 on transcription factor (TF) binding were tested by DNA pull-down and quantitative mass spectrometry. The results were validated by electrophoretic mobility gel shift assays (EMSA), Western blot (WB) analysis of the pulled-down eluates, and chromatin immuno-precipitation (ChIP)-qPCR.ResultsSeveral TFs showed differential allelic binding to a 50bp DNA probe spanning rs4648889. Binding was increased to the AS-risk A allele for IKZF3 (aiolos) in nuclear extracts from CD8+ T-cells (3.7-fold, p<0.03) and several components of the NUcleosome Remodeling Deacetylase (NuRD) complex, including Chromodomain-Helicase-DNA-binding protein 4 (3.6-fold, p<0.05) and Retinoblastoma-Binding Protein 4 (4.1-fold, p<0.02). In contrast, binding of interferon regulatory factor (IRF) 5 was increased to the AS-protective G allele. These results were confirmed by EMSA, WB and ChIP-qPCR.ConclusionsThe association of AS with rs4648889 most likely results from its influence on the binding of this enhancer-like region to TFs, including IRF5, IKZF3 and members of the NuRD complex. Further investigation of these factors and RUNX3-related pathways may reveal important new therapeutic possibilities in AS.

Chromatin bound by survivin regulates the glycolytic switch in interferon-γ producing CD4+ T cells

2021 ◽  
Author(s):  
Malin Erlandsson ◽  
Karin Andersson ◽  
Nina Oparina ◽  
Venkataragavan Chandrasekaran ◽  
Anastasios Damdimopoulos ◽  
...  
Keyword(s):  
T Cells ◽  
Glucose Utilization ◽  
Interferon Γ ◽  
Interferon Regulatory Factor ◽  
Metabolic Adaptation ◽  
Regulatory Factor ◽  
Cell Functions ◽  
Interferon Regulatory Factor 1 ◽  
Direct Binding ◽  
Nuclear Survivin

Abstract Upon activation, CD4+ T cells adapt metabolically to fulfill their effector function in autoimmunity. Here we show that nuclear survivin is essential for transcriptional regulation of glucose utilization. We found that the glycolytic switch in interferon (IFN) g–producing CD4+ cells is dependent on a complex of survivin with interferon regulatory factor 1 (IRF1), and Smad3 and was reversed by survivin inhibition. Transcriptome analysis of CD4+ cells and sequencing of survivin-bound chromatin identified a hub of metabolism regulating genes whose transcription depended on survivin. Direct binding of survivin to IRF1 and SMAD3 promoted IRF1-mediated transcription, repressed SMAD3 activity, and lowered PFKFB3 production. Inhibiting survivin upregulated PFKFB3, restored glycolysis, and reduced glucose uptake, improving control over IFNg-dependent T-cell functions. Thus, IRF1-survivin-SMAD3 interactions are important for metabolic adaptation of CD4+ cells and provide an attractive strategy to counteract IFNg-dependent inflammation.

scholarly journals Pulmonary Inflammation Induced by Pseudomonas aeruginosa Lipopolysaccharide, Phospholipase C, and Exotoxin A: Role of Interferon Regulatory Factor 1

2002 ◽  
Vol 70 (3) ◽  
pp. 1352-1358 ◽  
Author(s):  
Catharina W. Wieland ◽  
Britta Siegmund ◽  
Giorgio Senaldi ◽  
Michael L. Vasil ◽  
Charles A. Dinarello ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Pulmonary Inflammation ◽  
Interferon Regulatory Factor ◽  
Cell Infiltration ◽  
Exotoxin A ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Chronic pulmonary infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) patients. P. aeruginosa lipopolysaccharide (LPS), phosholipase C (PLC), and exotoxin A (ETA) were evaluated for their ability to induce pulmonary inflammation in mice following intranasal inoculation. Both LPS and PLC induced high levels of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), IL-6, gamma interferon (IFN-γ), MIP-1α and MIP-2 in the lungs but did not affect IL-18 levels. ETA did not induce TNF-α and was a weak inducer of IL-1β, IL-6, macrophage inflammatory protein 1α (MIP-1α), and MIP-2. Remarkably, ETA reduced constitutive lung IL-18 levels. LPS was the only factor inducing IFN-γ. LPS, PLC, and ETA all induced cell infiltration in the lungs. The role of interferon regulatory factor-1 (IRF-1) in pulmonary inflammation induced by LPS, PLC, and ETA was evaluated. When inoculated with LPS, IRF-1 gene knockout (IRF-1 KO) mice produced lower levels of TNF-α, IL-1β, and IFN-γ than did wild-type (WT) mice. Similarly, a milder effect of ETA on IL-1β and IL-18 was observed for IRF-1 KO than for WT mice. In contrast, the cytokine response to PLC did not differ between WT and IRF-1 KO mice. Accordingly, LPS and ETA, but not PLC, induced expression of IRF-1 mRNA. IRF-1 deficiency had no effect on MIP-1α and MIP-2 levels and on cell infiltration induced by LPS, PLC, or ETA. Flow cytometric evaluation of lung mononuclear cells revealed strongly reduced percentages of CD8+ and NK cells in IRF-1 KO mice compared to percentages observed for WT mice. These data indicate that different virulence factors from P. aeruginosa induce pulmonary inflammation in vivo and that IRF-1 is involved in some of the cytokine responses to LPS and ETA.

Central role of interferon regulatory factor-1 (IRF-1) in controlling retinoic acid inducible gene-I (RIG-I) expression

2007 ◽  
Vol 213 (2) ◽  
pp. 502-510 ◽  
Author(s):  
Zao-Zhong Su ◽  
Devanand Sarkar ◽  
Luni Emdad ◽  
Paola M. Barral ◽  
Paul B. Fisher
Keyword(s):  
Retinoic Acid ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
Inducible Gene
Sign in / Sign up

Export Citation Format

Share Document