The regulation role of interferon regulatory factor-1 gene and clinical relevance

doi:10.1016/j.humimm.2014.09.015

Human Immunology

Volume 75, Issue 11, November 2014, Pages 1110-1114

https://doi.org/10.1016/j.humimm.2014.09.015 Get rights and content

Abstract

IRF-1, a kind of transcription factors, is expressed constitutively in all cells types except early embryonal cells. By virtue of its interaction with specific DNA sequence, IRF-1 regulates the transcription of a set of target genes which play essential roles in various physiological and pathological processes, including viral infection, tumor immune surveillance, pro-inflammatory injury, development of immunity system. What’s more, IRF-1 also interacts with other transcription factors to regulate the specific genes transcription in the nucleus. In immunity system, IRF-1 is suggested to provide a link between innate and adoptive immune system. Although IRF-1 has been demonstrated with essential role in human immunity, the comprehensive understanding of the role of IRF-1 has been restrained because of extensive target genes, Here, we review the clinical relevance of IRF-1 and underlying mechanism based on the latest researches.

Introduction

Interferon regulatory factor (IRF)-1, the first member of the interferon (IFN) regulatory factor family, was originally identified as a key regulator of type I interferon (α/β). IRF-1 messenger RNA (mRNA) is expressed constitutively in cell cycle-dependent accumulation at a low base level in all cells types except early embryonal cells, but IRF-1 protein has a short half-life of 30 min [1]. IRF-1 levels are markedly regulated at the transcriptional level in response to various stimuli such as IFNs (type I and type II), double-stranded RNA, cytokines, and hormones. The DNA-binging domains (DBDs) of IRF-1 are located in the first 115 amino acids of the amino-terminal region characterized by a series of five well-conserved tryptophan-rich repeats. The DBD forms a helix-turn-helix domain and recognizes a DNA sequence similar to the IFN-stimulated response element (A/GNGAAANNGAAACT) [2], [3]. IRF-1 may bind DNA either as a monomer or as a dimer [4]. By virtue of its affinity of specific DNA sequence, IRF-1 was described to participate in transcription of various IRF-1-induced genes [5]. Besides that, IRF-1 also contains a carboxy(C)-terminal IRF-association domain (IAD), which is less well-conserved and facilitates heterodimerization between family members, interaction with transcription factors and cofactors [6].

Other functional domains also contribute to a balanced activity of IRF-1 as shown in Fig. 1. IRF-1 contains two potential sequences which might act as nuclear location signal (NLS), RKERKSK and KSKTKRK, which is required and is sufficient to translocate IRF-1 from the site of synthesis in the cytoplasm to the nucleus [7]. A C-terminal fragment of IRF-1 has no activator function by itself but acts as a strong enhancer of activator sequences. The N-terminal 60 amino acids of IRF-1 strongly inhibit its transcriptional activity as a repression domain [8].

By the activities of all these functional domains, IRF-1 is suggested to provide a link between innate and adoptive immune system and plays a critical role in various physiological and pathological aspects, including viral infection, oncogenesis, pro-inflammatory injury, development of immune system and autoimmunity. This review focuses on the regulation role of IRF-1 in some specific topics. Improved understanding the role of IRF-1 that led to some pathological processes may aid development of novel therapeutic strategies.

Section snippets

IRF-1 in anti-infection immune responses

Type I IFN (IFN-α/β), one of the most important target genes of IRF-1, provides a crucial mechanism of anti-infection response [9]. As the discovery of pattern recognition receptors (PRRs), IRFs gained much attention as essential regulators of anti-infection response. PRRs recognize various pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS) and viral nuclear acids [10]. Two classes of PRR have been defined: the transmembrane PRRs, namely Toll-like receptors

IRF-1 in tumor immune surveillance

Accumulating evidences have indicated the contribution of IRF-1 to tumor immune surveillance in human. IRF-1 inactivation by deletion of its one or more exons (exon skipping) has demonstrated in many hematological malignancies, including acute myelocytic leukemia (AML) and myelodysplastic syndromes (MDS) [22]. The loss of one IRF-1 allele has been reported in esophageal and gastric cancers and the frequent loss of heterozygosity of IRF-1 gene was also demonstrated in sporadic breast cancer [23]

IRF-1 in pro-inflammatory injury

Previous studies have demonstrated that IRF-1 involved in injury in many clinical setting, including ischemia–reperfusion injury (IR), transplantation, shock. In liver warm IR model, IRF-1 knockout mice are protected from organ injury after IR and that over-expression of IRF-1 results in liver damage even in the absence of ischemia [52]. It is also proposed that reactive oxygen species (ROS)-induced renal tubular expression of IRF-1 exacerbates damage in acute kidney injury (AKI) [53]. The

IRF-1 in development of immune system and autoimmunity

In addition to the functions ascribe to IRF-1 in regulation of expression of various genes whose products are central to immunological response, previous studies have revealed roles for IRF-1 in the development of various immune cells, including NK cells, mature CD8+ T cells and differentiation of Th1 cells.

IRF-1 affects the development and function of NK cells. Analysis of the spleen and liver of IRF1−/− mice demonstrates a reduction in NK cell counts and function. It was demonstrated that the

Conclusion

This review summarize the contribution of IRF-1 involving in various physiological and pathological aspects, including viral infection, tumor immune surveillance, pro-inflammatory injury, development of immune system and autoimmune disease. What’ more, it also introduces the mechanism underlying IRF-1 mediated reaction and the interactions with other transcription factors. In one side, it is helpful to clarify the regulation role of IRF-1 in some specific clinical settings. In the other side,

References (72)

M. Miyamoto et al.
Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements
Cell
(1988)
S. Kirchhoff et al.
In vivo formation of IRF-1 homodimers
Biochimie
(1998)
S. Akira et al.
Pathogen recognition and innate immunity
Cell
(2006)
T. Matsuyama et al.
Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development
Cell
(1993)
J. Spink et al.
Binding of the transcription factor interferon regulatory factor-1 to the inducible nitric-oxide synthase promoter
J Biol Chem
(1997)
R. Koetzler et al.
Nitric oxide inhibits IFN regulatory factor 1 and nuclear factor-kappaB pathways in rhinovirus-infected epithelial cells
J Allergy Clin Immunol
(2009)
S. Ogasawara et al.
Common deleted region on the long arm of chromosome 5 in esophageal carcinoma
Gastroenterology
(1996)
C. Ruiz-Ruiz et al.
The up-regulation of human caspase-8 by interferon-gamma in breast tumor cells requires the induction and action of the transcription factor interferon regulatory factor-1
J Biol Chem
(2004)
X. Li et al.
Formation of STAT1–STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon-alpha
J Biol Chem
(1996)
E.N. Noon-Song et al.
Controlling nuclear JAKs and STATs for specific gene activation by IFN gamma
Biochem Biophys Res Commun
(2011)

J. Harris

Autophagy and cytokines

Cytokine

(2011)

P. Li et al.

Interferon gamma induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma (HCC) cells through interferon regulatory factor-1 (IRF-1)

Cancer Lett

(2012)

K.H. Kim et al.

Donor graft interferon regulatory factor-1 gene transfer worsens liver transplant ischemia/reperfusion injury

Surgery

(2009)

Y. Zhai et al.

Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation

Am J Transplant

(2011)

J.R. Klune et al.

Molecular biology of liver ischemia/reperfusion injury: established mechanisms and recent advancements

Surg Clin North Am

(2010)

H.J. Lee et al.

The role of STAT1/IRF-1 on synergistic ROS production and loss of mitochondrial transmembrane potential during hepatic cell death induced by LPS/d-GalN

J Mol Biol

(2007)

L. Shao et al.

Transcriptional suppression of cytokine-induced iNOS gene expression by IL-13 through IRF-1/ISRE signaling

Biochem Biophys Res Commun

(2007)

G. Trinchieri

Biology of natural killer cells

Adv Immunol

(1989)

L.C. White et al.

Regulation of LMP2 and TAP1 genes by IRF-1 explains the paucity of CD8+ T cells in IRF-1−/− mice

Immunity

(1996)

J.M. Penninger et al.

The interferon regulatory transcription factor IRF-1 controls positive and negative selection of CD8+ thymocytes

Immunity

(1997)

M. Lohoff et al.

Interferon regulatory factor-1 is required for a T helper 1 immune response in vivo

Immunity

(1997)

S. Taki et al.

Multistage regulation of Th1-type immune responses by the transcription factor IRF-1

Immunity

(1997)

N. Watanabe et al.

Activation of IFN-beta element by IRF-1 requires a posttranslational event in addition to IRF-1 synthesis

Nucleic Acids Res

(1991)

T. Fujita et al.

Evidence for a nuclear factor(s), IRF-1, mediating induction and silencing properties to human IFN-beta gene regulatory elements

EMBO J

(1988)

C.R. Escalante et al.

Structure of IRF-1 with bound DNA reveals determinants of interferon regulation

Nature

(1998)

F. Schaper et al.

Functional domains of interferon regulatory factor I (IRF-1)

Biochem J

(1998)

R. Pine et al.

Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either

Mol Cell Biol

(1990)

S. Kirchhoff et al.

Interplay between repressing and activating domains defines the transcriptional activity of IRF-1

Eur J Biochem/FEBS

(2000)

M. Colonna

TLR pathways and IFN-regulatory factors: to each its own

Eur J Immunol

(2007)

C.A. Janeway et al.

Innate immune recognition

Annu Rev Immunol

(2002)

M. Yoneyama et al.

The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

Nat Immunol

(2004)

M. Yoneyama et al.

Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity

J Immunol

(2005)

J. Pflugheber et al.

Regulation of PKR and IRF-1 during hepatitis C virus RNA replication

Proc Natl Acad Sci U S A

(2002)

F. Schmitz et al.

Interferon-regulatory-factor 1 controls Toll-like receptor 9-mediated IFN-beta production in myeloid dendritic cells

Eur J Immunol

(2007)

H. Negishi et al.

Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program

Proc Natl Acad Sci U S A

(2006)

K.R. Morris et al.

Role of the NF-kappaB signaling pathway and kappaB cis-regulatory elements on the IRF-1 and iNOS promoter regions in mycobacterial lipoarabinomannan induction of nitric oxide

Infect Immun

(2003)

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As an important member of the IRF family, IRF1 induces the expression of many genes, including interferon-γ (IFN-γ), interferon-λ, optineurin, P53, toll-like receptors 3, interferon-inducible protein 10, ISG20, viperin and MHC I [6]. These genes play the roles in immune response to viral infection, tumor immune monitoring and pro-inflammatory injury [7]. IRF1 regulates the expression of guanylate-binding protein and MHC I through type I and type II IFN stimulation.
Interferon regulatory factors (IRFs) are a family of transcription factors that play a role in a variety of biological processes including immune regulation of interferon and expression of inflammatory cytokines. However, the data on IRFs are rather limited in chickens. In the present study, qRT-PCR was used to study the tissue distribution of IRFs in chickens at D15 (the 15th day of raising) and developmental changes of all chIRFs (Chicken interferon regulatory factors) in BF from E15 (the 15th day of incubation) to D15. The effects of IBDV infection with chickens on the transcriptional level of chIRFs were also investigated. The results showed: (1) chIRF1 mRNA was expressed much more abundantly in intestinal tract, chIRF2, chIRF6, chIRF7, chIRF8 and chIRF10 distributed mainly in liver or/and kidney. The expression of chIRF5 was mainly in spleen and chIRF4 distributed uniquely abundantly in BF. (2) The mRNA expression levels of chIRF5, chIRF7, chIRF8 and chIRF10 was low before hatching of chicken and at D1 and increased significantly from D5 till to the experiment end and the fold change of chIRF5 at D10 and chIRF7 at D5 reached 41.0-fold and 15.7-fold compared to that of E15, respectively (P < 0.05). ChIRF4 mRNA level was always high during the whole experiment except for E15 and it was 11.9-fold at the highest time point than that of E15 (the lowest time point). (3) When chicken was infected with IBDV, the expression levels of chIRF2, chIRF7 and chIRF10 mRNA had the tendency of increasing first and then decreasing but they peaked at 1dpi, 2 dpi, and 3dpi, respectively. The expression of chIRF5 mRNA was suppressed obviously during the whole experiment stage in IBDV-infected chicken. And chIRF4 expression was up-regulated transitorily at 1dpi and then was suppressed on a very low level till to the experiment end. Conclusion: The chIRFs were constitutively expressed in different tissues examined and has tissue-specific expression. Of them, chIRF2, chIRF4, chIRF5, chIRF7, chIRF8 and chIRF10 were related closely with the development or immune response of BF, and when chicken was infected with IBDV, some of them were activated, earlier or later on, some of them were suppressed. These findings would help to sieve out a few antiviral chIRF candidate gene to improve the host's innate immune and provide a foundation of the further exploiting a new vaccine adjuvant.
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Interferon regulatory factor-1 (IRF-1) is a nuclear transcription regulator that serves as an activator of genes implicated in the regulation of interferon expression, the regulation of both innate and acquired immunity, and lymphocyte differentiation [13]. IRF-1 is also a tumour suppressor and plays an important role in cell proliferation, apoptosis and the DNA damage response by regulating the expression of various genes, such as P21, P53, and caspases [13,14]. Although IRF-1 has been extensively studied in studies aiming to inhibit tumour cell proliferation and apoptosis, few studies have investigated the role of IRF-1 in tumour cell chemoresistance, and their conclusions are contradictory.
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¹: Yi-Fa Chen and Xiao-Ping Chen are co-communicating authors.

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ReviewThe regulation role of interferon regulatory factor-1 gene and clinical relevance

Abstract

Introduction

Section snippets

IRF-1 in anti-infection immune responses

IRF-1 in tumor immune surveillance

IRF-1 in pro-inflammatory injury

IRF-1 in development of immune system and autoimmunity

Conclusion

Cell

Biochimie

Cell

Cell

J Biol Chem

J Allergy Clin Immunol

Gastroenterology

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

Cytokine

Cancer Lett

Surgery

Am J Transplant

Surg Clin North Am

J Mol Biol

Biochem Biophys Res Commun

Adv Immunol

Immunity

Immunity

Immunity

Immunity

Activation of IFN-beta element by IRF-1 requires a posttranslational event in addition to IRF-1 synthesis

Nucleic Acids Res

Evidence for a nuclear factor(s), IRF-1, mediating induction and silencing properties to human IFN-beta gene regulatory elements

EMBO J

Structure of IRF-1 with bound DNA reveals determinants of interferon regulation

Nature

Functional domains of interferon regulatory factor I (IRF-1)

Biochem J

Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either

Mol Cell Biol

Interplay between repressing and activating domains defines the transcriptional activity of IRF-1

Eur J Biochem/FEBS

TLR pathways and IFN-regulatory factors: to each its own

Eur J Immunol

Innate immune recognition

Annu Rev Immunol

The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

Nat Immunol

Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity

J Immunol

Regulation of PKR and IRF-1 during hepatitis C virus RNA replication

Proc Natl Acad Sci U S A

Interferon-regulatory-factor 1 controls Toll-like receptor 9-mediated IFN-beta production in myeloid dendritic cells

Eur J Immunol

Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program

Proc Natl Acad Sci U S A

Role of the NF-kappaB signaling pathway and kappaB cis-regulatory elements on the IRF-1 and iNOS promoter regions in mycobacterial lipoarabinomannan induction of nitric oxide

Infect Immun

Review
The regulation role of interferon regulatory factor-1 gene and clinical relevance