A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders

doi:10.1016/j.mrfmmm.2009.09.007

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis

Volume 690, Issues 1–2, 7 August 2010, Pages 12-23

https://doi.org/10.1016/j.mrfmmm.2009.09.007 Get rights and content

Abstract

Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor that plays a central role in cellular defense against oxidative and electrophilic insults by timely induction of antioxidative and phase-2 detoxifying enzymes and related stress–response proteins. The 5′-flanking regions of genes encoding these cytoprotective proteins contain a specific consensus sequence termed antioxidant response element (ARE) to which Nrf2 binds. Recent studies have demonstrated that Nrf2–ARE signaling is also involved in attenuating inflammation-associated pathogenesis, such as autoimmune diseases, rheumatoid arthritis, asthma, emphysema, gastritis, colitis and atherosclerosis. Thus, disruption or loss of Nrf2 signaling causes enhanced susceptibility not only to oxidative and electrophilic stresses but also to inflammatory tissue injuries. During the early-phase of inflammation-mediated tissue damage, activation of Nrf2–ARE might inhibit the production or expression of pro-inflammatory mediators including cytokines, chemokines, cell adhesion molecules, matrix metalloproteinases, cyclooxygenase-2 and inducible nitric oxide synthase. It is likely that the cytoprotective function of genes targeted by Nrf2 may cooperatively regulate the innate immune response and also repress the induction of pro-inflammatory genes. This review highlights the protective role of Nrf2 in inflammation-mediated disorders with special focus on the inflammatory signaling modulated by this redox-regulated transcription factor.

Introduction

Nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a redox-sensitive transcription factor, which belongs to the cap ‘n’ collar subfamily containing the basic leucine zipper region [1]. Nrf2 binds to antioxidant response elements (ARE) located in the promoter region of genes encoding many phase II detoxifying or antioxidant enzymes and related stress-responsive proteins [1]. These include NAD(P)H:quinone oxidoreductase (NQO1), glutathione S-transferase (GST), heme oxygenase-1 (HO-1), glutathione peroxidase (GPx), glutamate cysteine ligase (GCL), and peroxiredoxin I (Prx I) that play key roles in cellular defense by enhancing the removal of cytotoxic electrophiles or reactive oxygen species (ROS) [1]. Induction of these cytoprotective enzymes via Nrf2–ARE signaling hence provides an effective means for achieving cellular protection against a variety of electrophilic carcinogens and other reactive toxicants as well as ROS [2]. Since ROS- or electrophile-induced mutations are critical for carcinogenesis, Nrf2 has been recognized as one of the most important and promising molecular targets for chemoprevention [3].

In addition to protection against oxidative and electrophilic stresses, recent studies have demonstrated that Nrf2 responds to pro-inflammatory stimuli and rescues cells/tissues from inflammatory injuries [4], [5], [6], [7], [8], [9]. Thus, Nrf2 knockout mice develop complex pathogenic manifestations. These include lupus-like autoimmune syndrome characterized by multi-organ inflammatory lesions, intravascular deposition of immunoglobulin (Ig) complexes and premature death due to rapidly progressing glomerular nephritis [10]. Oligonucleotide microarray analysis has revealed that Nrf2 regulates the expression of acute phase proteins in the lung [11], whose plasma concentrations vary depending on the stage of inflammation, suggesting that Nrf2 may act as a critical mediator of cellular adaptation in response to pro-inflammatory as well as other noxious stimuli. Therefore, understanding the defense mechanism by which the Nrf2 activation confers protection against inflammation can provide rationale to develop therapeutic and preventive strategies for the management of inflammation-associated disorders. This review focuses mainly on the protective role of Nrf2 in inflammatory disorders and the key pro- and anti-inflammatory mediators whose production and/or functions are modulated by Nrf2–ARE signaling.

Section snippets

Molecular mechanisms underlying up-regulation of Nrf2/ARE-dependent genes

Under the basal resting condition, Nrf2 is sequestered in the cytoplasm by the cytoskeleton-associated protein, Kelch-like ECH-associated protein 1 (Keap1) (Fig. 1) [12]. Keap1 functions as a negative regulator of Nrf2 by promoting ubiquitination and proteasomal degradation of Nrf2 [13], [14]. When liberated from its repressor Keap1, Nrf2 translocates into the nucleus and forms a heterodimer with a small Maf (sMaf) protein [2], [15]. The Nrf2–sMaf dimer then binds to ARE, a cis-acting DNA

HO-1, an important anti-inflammatory and cytoprotective enzyme up-regulated by Nrf2

Among the enzymes up-regulated by Nrf2, HO-1 has pronounced anti-inflammatory as well as antioxidative properties. HO-1 promoter contains ARE, and the activation of Nrf2 enhances HO-1 expression in several cell types [27], [28], [29], [30]. Recent research has revealed that HO-1 is a critical regulator to modulate the innate immunity and inflammation. For instance, elevated HO-1 expression/activity has been observed in acute inflammatory illnesses, and monocyte HO-1 production is considered to

Cytokines

Some cytokines are regarded as pro-inflammatory mediators, whereas others have anti-inflammatory functions [1]. In response to oxidative stress, pro-inflammatory cytokines are often overproduced and they, in turn, can also cause oxidative stress in the target cells. Thus, several pro-ininflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-2, IL-6, and IL-12 are overproduced when redox-sensitive nuclear factor-κB (NF-κB) is activated by oxidative stress.

Cross-talk between Nrf2 and inflammatory signaling

Intracellular ROS including superoxide (O₂ radical dot ⁻), hydrogen peroxide (H₂O₂) and peroxynitrite (ONOO⁻), have a fundamental role in pro-inflammatory responses through activation of redox-sensitive transcription factors such as NF-κB and AP-1 and their up-regulating kinases including MAPKs (p38, ERK and JNK) and PI3K (reviewed in [73]). Since Nrf2–ARE-regulated genes contribute to cellular protection against oxidative stresses and to potentiation of antioxidant defense capacity in cells, modulation of

Nrf2 in inflammation-associated disorders

There are multiple lines of evidence supporting that inflammation, the body's most primitive arsenal developed to fight infection, is at the root of several degenerative human disorders, such as cancer, rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, Alzheimer's disease, multiple sclerosis, type I diabetes mellitus, etc. [60]. Inflammation occurs as part of the immune reaction and produces ROS to fight against the invading pathogens and to

Concluding remarks

Nrf2-mediated up-regulation of antioxidative and other cytoprotective enzymes confers cellular protection against infections and inflammation by reducing deleterious production of pro-inflammatory mediators. HO-1, one of the representative stress-response enzymes up-regulated by Nrf2–ARE signaling, has been reported to exert anti-inflammatory as well as antioxidant effects. Activation of Nrf2 increases the gene expression of a distinct set of cytoprotectants that extinguish the ‘fires within’

Conflicts of interest

None.

Acknowledgements

This work was supported by the grant for 21C Frontier Functional Human Genome Project (Grant No. FG07-21-21), the Innovative Drug Research Center (Grant No. R11-2007-107-01002-0) from Korea Research Foundation, the Ministry of Education, Science and Technology, Republic of Korea.

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ReviewA protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders

Abstract

Introduction

Section snippets

Molecular mechanisms underlying up-regulation of Nrf2/ARE-dependent genes

HO-1, an important anti-inflammatory and cytoprotective enzyme up-regulated by Nrf2

Cytokines

Cross-talk between Nrf2 and inflammatory signaling

Nrf2 in inflammation-associated disorders

Concluding remarks

Conflicts of interest

Acknowledgements

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Am. J. Pathol.

J. Biol. Chem.

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Blood

J. Ethnopharmacol.

Mutat. Res.

Biochem. Pharmacol.

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Am. J. Pathol.

J. Biol. Chem.

Food Chem. Toxicol.

Biochem. Pharmacol.

Int. Rev. Neurobiol.

Kidney Int.

J. Biol. Chem.

Clin. Chest Med.

An important role of Nrf2–ARE pathway in the cellular defense mechanism

J. Biochem. Mol. Biol.

Cell survival responses to environmental stresses via the Keap1–Nrf2–ARE pathway

Annu. Rev. Pharmacol. Toxicol.

Cancer chemoprevention: scientific promise, clinical uncertainty

Nat. Clin. Pract. Oncol.

Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound

Mol. Cell. Biol.

The relationship between Helicobacter pylori infection and promoter polymorphism of the Nrf2 gene in chronic gastritis

Int. J. Mol. Med.

Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression

Am. J. Physiol. Heart Circ. Physiol.

Role of NRF2 in protection against hyperoxic lung injury in mice

Am. J. Respir. Cell Mol. Biol.

The transcription factor NRF2 protects against pulmonary fibrosis

FASEB J.

Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain

Genes Dev.

BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase

Mol. Cell. Biol.

Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2

Mol. Cell. Biol.

Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins

Mol. Cell. Biol.

The role of Keap1 in cellular protective responses

Chem. Res. Toxicol.

Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers

Proc. Natl. Acad. Sci. U.S.A.

Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants

Proc. Natl. Acad. Sci. U.S.A.

Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane

Chem. Res. Toxicol.

Involvement of Nrf2 and JNK1 in the activation of antioxidant responsive element (ARE) by chemopreventive agent phenethyl isothiocyanate (PEITC)

Pharm. Res.

Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene

Proc. Natl. Acad. Sci. U.S.A.

Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo

Arterioscler. Thromb. Vasc. Biol.

Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult

J. Neurosci.

Review
A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders