Activation of the Nrf2/antioxidant response pathway increases IL-8 expression

Zhang, Xiaolan; Chen, Xilin; Song, Huijuan; Chen, Hui-Zi; Rovin, Brad H.

doi:10.1002/eji.200526116

Cited by 89 publications

(63 citation statements)

References 42 publications

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“…ROS neutralization may play a role in preventing a continuous PMN influx to allow for resolution of inflammation to proceed because PMN chemotaxis is a ROS-dependent process. 33,34 Nrf2 down-regulation in oPMNs of CP patients as cause for reduced PMN ability to neutralize ROS and withstand oxidative stress supports previous reports of increased oxidative damage in CP. 4,10 Interestingly, ingenuity pathway analysis predicted a more significant Nrf2 pathway down-regulation in blood PMNs of patients with CP compared with healthy controls.…”

Section: Discussionsupporting

confidence: 85%

Nuclear Factor Erythroid 2-Related Factor 2 Down-Regulation in Oral Neutrophils Is Associated with Periodontal Oxidative Damage and Severe Chronic Periodontitis

Sima

Aboodi

Lakschevitz

et al. 2016

The American Journal of Pathology

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The balance between reactive oxygen species and antioxidants plays an important role in periodontal health. We previously demonstrated that high reactive oxygen species production by oral polymorphonuclear neutrophils (oPMNs) in chronic periodontitis (CP) refractory to conventional therapy is associated with severe destruction of periodontium. Herein, we show that inhibition of antioxidant production through down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in oPMN, despite enhanced recruitment in the oral cavity, is associated with severe CP. Twenty-four genes in the Nrf2-mediated oxidative stress response pathway were down-regulated in PMNs of diseased patients. Downstream of Nrf2, levels of oPMN superoxide dismutase 1 and catalase were decreased in severe CP, despite increased recruitment. Nrf2 À/À mice had more severe loss of periodontium in response to periodontitis-inducing subgingival ligatures compared with wild-types. Levels of 8-hydroxydeoxyguanosine were increased in periodontal lesions of Nrf2 À/À mice, indicating high oxidative damage. We report, for the first time, Nrf2 pathway down-regulation in oPMNs of patients with severe CP. PMNs of CP patients may be primed for low antioxidant response in the context of high recruitment in the oral cavity, resulting in increased oxidative tissue damage. (Am J Pathol 2016 http://dx

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Section: Discussionsupporting

confidence: 85%

Nuclear Factor Erythroid 2-Related Factor 2 Down-Regulation in Oral Neutrophils Is Associated with Periodontal Oxidative Damage and Severe Chronic Periodontitis

Sima

Aboodi

Lakschevitz

et al. 2016

The American Journal of Pathology

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“…Because of their altered capacity to respond to IFN-g, but also to other cytokines locally released during psoriasis development, keratinocytes show abnormal hyperproliferation and differentiation, both responsible for the marked hyperplasia of psoriatic epidermis (25). In addition, in response to IFN-g, keratinocytes initiate a program of enhanced or de novo expression of a plethora of inflammatory mediators involved in the recruitment and local activation of immune cells in psoriatic skin (26)(27)(28)(29). Similar to other cell types, in human keratinocytes IFN-g signaling triggers a series of molecular cascades initiated by Jak1 and Jak2 proteins, which culminates with the activation of transcription factors, mainly STAT1 and IRF-1, regulating a number of IFN-g-dependent genes (30).…”

Section: Discussionmentioning

confidence: 99%

The IFN-γ–Dependent Suppressor of Cytokine Signaling 1 Promoter Activity Is Positively Regulated by IFN Regulatory Factor-1 and Sp1 but Repressed by Growth Factor Independence-1b and Krüppel-Like Factor-4, and It Is Dysregulated in Psoriatic Keratinocytes

Madonna¹,

Scarponi²,

Sestito³

et al. 2010

The Journal of Immunology

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Epidermal keratinocytes can counteract the detrimental effects of IFN-γ by inducing the expression of suppressor of cytokine signaling (SOCS)1, which plays an important anti-inflammatory and self-protective role. To date, limited information exists on its expression and regulation in human diseased keratinocytes. In this study, we compared the expression levels of SOCS1 in keratinocytes isolated from skin affected by psoriasis with cells obtained from healthy donors, unveiling that keratinocytes are more prone than healthy cells to upregulate SOCS1 mRNA expression in response to IFN-γ. We explored the regulatory mechanisms involved in socs1 gene transcription, and found that Sp1 and IFN regulatory factor-1 transcription factors are, respectively, responsible for the basal and IFN-γ–induced activity of human socs1 promoter. In parallel, we demonstrated that socs1 promoter is negatively regulated by two transcriptional repressors, namely, growth factor independence-1b and Krüppel-like factor 4, which tightly control SOCS1 transcription on IFN-γ stimulation. Interestingly, although the expression of Sp1 and IFN regulatory factor-1 activators of socs1 promoter is unaltered, growth factor independence-1b and Krüppel-like factor 4 are significantly reduced in psoriatic compared with healthy keratinocytes. This reduction and the consequent unbalanced binding of transcriptional activators and repressors to socs1 promoter after IFN-γ stimulation might be responsible for the enhanced expression of SOCS1 in psoriatic cells. We suggest that SOCS1 exaggerated upregulation in psoriatic keratinocytes could represent a mechanism through which these cells attempt to protect themselves from IFN-γ effects. However, the SOCS1 increased levels in psoriatic keratinocytes are not sufficient to completely inhibit the expression of proinflammatory genes.

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“…It has been reported that Nrf2, a key regulator of cell survival [6,7], can induce and up-regulate cytoprotective and antioxidant genes that attenuate tissue injury [8,9]. Sulforaphane, a naturally occurring isothiocyanate that induces the expression of multiple Nrf2-responsive genes, has been shown to be neuroprotective against focal cerebral ischemia in rats [10].…”

Section: Introductionmentioning

confidence: 99%

Role of Nrf2 in protection against intracerebral hemorrhage injury in mice

Wang

Fields

Zhao

et al. 2007

Free Radical Biology and Medicine

201

177

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Nrf2 is a key transcriptional factor for antioxidant response element (ARE)-regulated genes. While its beneficial role has been described for stroke, its contribution to intracerebral hemorrhage (ICH)-induced early brain injury remains to be determined. Using wildtype (WT) and Nrf2 knockout (Nrf2 −/− ) mice, the role of Nrf2 in ICH induced by intracerebral injection of collagenase was investigated. The results showed that injury volume was significantly larger in Nrf2 −/− mice than in WT controls 24 h after induction of ICH (p < 0.05), an outcome that correlated with neurological deficits. This exacerbation of brain injury in Nrf2 −/− mice was also associated with an increase in leukocyte infiltration, production of reactive oxygen species, DNA damage, and cytochrome c release during the critical early phase of the post-ICH period. In combination, these results suggest that Nrf2 reduces ICH-induced early brain injury, possibly by providing protection against leukocyte-mediated free radical oxidative damage.

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Activation of the Nrf2/antioxidant response pathway increases IL-8 expression

Cited by 89 publications

References 42 publications

Nuclear Factor Erythroid 2-Related Factor 2 Down-Regulation in Oral Neutrophils Is Associated with Periodontal Oxidative Damage and Severe Chronic Periodontitis

Nuclear Factor Erythroid 2-Related Factor 2 Down-Regulation in Oral Neutrophils Is Associated with Periodontal Oxidative Damage and Severe Chronic Periodontitis

The IFN-γ–Dependent Suppressor of Cytokine Signaling 1 Promoter Activity Is Positively Regulated by IFN Regulatory Factor-1 and Sp1 but Repressed by Growth Factor Independence-1b and Krüppel-Like Factor-4, and It Is Dysregulated in Psoriatic Keratinocytes

Role of Nrf2 in protection against intracerebral hemorrhage injury in mice

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