Altered Immune Response of Interferon Regulatory Factor 1-Deficient Mice against Plasmodium berghei Blood-Stage Malaria Infection

1999 ◽  
Vol 67 (5) ◽  
pp. 2277-2283 ◽  
Author(s):  
Rosemary Sok-Pin Tan ◽  
Chiguang Feng ◽  
Yoshihiro Asano ◽  
Anna Ursula Kara
Keyword(s):  
Nitric Oxide ◽  
Immune Response ◽  
Plasmodium Berghei ◽  
Interferon Regulatory Factor ◽  
Blood Stage ◽  
Wild Type ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
In The Wild ◽  
Ifn Γ

ABSTRACT Nitric oxide (NO) is a short-lived biological mediator which can be induced in various cell types and is able to cause many metabolic changes in target cells. Inhibition of tumor cell growth and antimicrobial activity has been attributed to the stimulation of NO production by transcriptional upregulation of inducible nitric oxide synthase. In the present study, we used mice devoid of functional interferon regulatory factor 1 by targeted gene disruption (IRF-1−/−) to investigate the role of NO in the host immune response against blood-stage Plasmodium berghei ANKA infection. IRF-1−/− mice survived longer with a later onset of and a lower peak parasitemia despite the inability to produce appreciable levels of NO. The administration of exogenous interleukin-12 (IL-12) was able to prolong survival in the wild-type mice with an upregulation in the expression of both gamma interferon (IFN-γ) and NO. However, the administration of IL-12 did not improve the survival of IRF-1−/− mice. These studies indicate that while IL-12 is able to mediate protection via an IFN-γ- and NO-dependent pathway in the wild-type mice, such a protective mechanism may not be functional in the IRF-1−/− mice. Our results suggest that NO may not be essential for host immunity to the parasite and that IRF-1−/− mice are able to induce an IFN-γ- and NO-independent mechanism against P. berghei infection.

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 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.

Cytokine-inducible CD40 expression in human endothelial cells is mediated by interferon regulatory factor-1

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 520-525 ◽  
Author(s):  
Andreas H. Wagner ◽  
Matthias Gebauer ◽  
Beatrix Pollok-Kopp ◽  
Markus Hecker
Keyword(s):  
Endothelial Cells ◽  
De Novo ◽  
Cd40 Ligand ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
De Novo Synthesis ◽  
Human Endothelial Cells ◽  
Interferon Regulatory Factor 1 ◽  
Ifn Γ ◽  
Cd40 Expression

Abstract Given the significance of CD40–CD40 ligand interactions in chronic inflammatory diseases including atherosclerosis, the transcriptional regulation of CD40 expression as a potential therapeutic target was investigated in human umbilical vein cultured endothelial cells. Exposure to interferon-γ (IFN-γ) plus tumor necrosis factor-α resulted in a marked synergistic de novo expression of CD40, which, according to electrophoretic mobility shift analysis, was attributable to activation of the transcription factors nuclear factor-κB (NF-κB), signal transducer and activator of transcription-1 (STAT-1), and interferon regulatory factor-1 (IRF-1). Subsequent time-course studies revealed that de novo synthesis of IRF-1 preceded that of CD40. Decoy oligodeoxynucleotide (ODN) neutralization of STAT-1 or IRF-1, but not of NF-κB, inhibited cytokine-stimulated CD40 expression by 60% at both the mRNA and protein levels, and this effect was mimicked by antisense ODN blockade of IRF-1 synthesis. In contrast, CD40 expression in response to IFN-γ stimulation was sensitive to neutralization of STAT-1 only. These findings suggest that depending on the cytokine composition, CD40 expression in human endothelial cells under proinflammatory conditions is governed by STAT-1 either directly or indirectly through de novo synthesis of IRF-1. Moreover, decoy ODN neutralization of these transcription factors may provide a novel therapeutic option for interfering with CD40–CD40 ligand-mediated inflammatory responses in vivo.

scholarly journals Interferon regulatory factor 1 priming of tumour-derived exosomes enhances the antitumour immune response

2017 ◽  
Vol 118 (1) ◽  
pp. 62-71 ◽  
Author(s):  
Mu-qing Yang ◽  
Qiang Du ◽  
Patrick R Varley ◽  
Julie Goswami ◽  
Zhihai Liang ◽  
...  
Keyword(s):  
Immune Response ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1

scholarly journals 17β-Estradiol downregulates interferon regulatory factor-1 in murine splenocytes

2006 ◽  
Vol 37 (3) ◽  
pp. 421-432 ◽  
Author(s):  
Andrea J Lengi ◽  
Rebecca A Phillips ◽  
Ebru Karpuzoglu ◽  
Sattar Ansar Ahmed
Keyword(s):  
T Cells ◽  
Interferon Regulatory Factor ◽  
Lymphoid Cells ◽  
Regulatory Factor ◽  
Murine Splenocytes ◽  
Potent Inducer ◽  
Interferon Regulatory Factor 1 ◽  
17Β Estradiol ◽  
Ifn Γ ◽  
In Cells

Interferon regulatory factor-1 (IRF-1) is an important transcription factor that mediates interferon-γ (IFN-γ)-induced cell-signaling events. In this study, we examined whether 17β-estradiol alters IRF-1 in splenic lymphocytes, in view of the immunomodulatory effects of this natural female sex hormone including its ability to alter IFN-γ levels. We find that IRF-1 expression is markedly downregulated in splenocytes or purified T-cells from estrogen-treated mice at all time points studied when compared with their placebo counterparts. This decrease in IRF-1 in splenocytes from estrogen-treated mice is neither due to upregulation of IRF-1-interfering proteins (nucleophosmin or signal transducer and activator of transcription (STAT)-5) nor due to alternatively spliced IRF-1 mRNA. Given that IFN-γ is a potent inducer of IRF-1, direct addition of recombinant IFN-γ to splenocytes from either wild-type or IFN-γ-knockout mice, or the addition of recombinant IFN-γ to purified T-cells, was expected to stimulate IRF-1 expression. However, robust expression of IRF-1 in cells from estrogen-treated mice was not seen, unlike what was observed in cells from placebo-treated mice. Diminished IFN-γ induction of IRF-1 in cells from estrogen-treated mice was noticed despite comparable phosphorylated STAT-1 activation. These studies are the first to show that estrogen regulates IFN-γ-inducible IRF-1 in lymphoid cells, a finding that may have implications to IFN-γ-regulated immune and vascular diseases.

scholarly journals Crucial Role of Interferon Consensus Sequence Binding Protein, but neither of Interferon Regulatory Factor 1 nor of Nitric Oxide Synthesis for Protection Against Murine Listeriosis

1997 ◽  
Vol 185 (5) ◽  
pp. 921-932 ◽  
Author(s):  
Thomas Fehr ◽  
Gabriele Schoedon ◽  
Bernhard Odermatt ◽  
Thomas Holtschke ◽  
Markus Schneemann ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Binding Protein ◽  
Consensus Sequence ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Oxygen Intermediates ◽  
Ifn Γ ◽  
Effector Mechanisms

Listeria monocytogenes is widely used as a model to study immune responses against intracellular bacteria. It has been shown that neutrophils and macrophages play an important role to restrict bacterial replication in the early phase of primary infection in mice, and that the cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) are essential for protection. However, the involved signaling pathways and effector mechanisms are still poorly understood. This study investigated mouse strains deficient for the IFN-dependent transcription factors interferon consensus sequence binding protein (ICSBP), interferon regulatory factor (IRF)1 or 2 for their capacity to eliminate Listeria in vivo and in vitro and for production of inducible reactive nitrogen intermediates (RNI) or reactive oxygen intermediates (ROI) in macrophages. ICSBP−/− and to a lesser degree also IRF2−/− mice were highly susceptible to Listeria infection. This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-γ in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-γ stimulation, whereas nitric oxide production was normal. In contrast, mice deficient for IRF1 were not able to produce nitric oxide, but they efficiently controlled Listeria in vivo and in vitro. These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-γ–mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.

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