Nuclear Factor-κB (NF-κB) Inhibitory Protein IκBβ Determines Apoptotic Cell Death following Exposure to Oxidative Stress

Wright, Clyde J.; Agboke, Fadeke A.; Muthu, Manasa; Michaelis, Katherine A.; Mundy, Miles; La, Ping; Guang, Yang; Dennery, Phyllis A.

doi:10.1074/jbc.m111.318246

Cited by 24 publications

(22 citation statements)

References 32 publications

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“…Previous studies have shown that NF-kB activity prevents cell death induced by various types of oxidant stress. These include ischemia-reperfusion to the intestine and heart (16,17,19), oxidant stress induced by H 2 O 2 in A549 cells (18), and glucose oxidase in murine embryonic fibroblast cells (37). In addition, enhanced hyperoxiainduced NF-kB activation explains the resistance to lung injury seen in neonatal mice, in part due to inhibition of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

IκBβ-Mediated NF-κB Activation Confers Protection against Hyperoxic Lung Injury

Michaelis

Agboke

Liu

et al. 2014

Am J Respir Cell Mol Biol

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Supplemental oxygen is frequently used in an attempt to improve oxygen delivery; however, prolonged exposure results in damage to the pulmonary endothelium and epithelium. Although NF-kB has been identified as a redox-responsive transcription factor, whether NF-kB activation exacerbates or attenuates hyperoxic lung injury is unclear. We determined that sustained NF-kB activity mediated by IkBb attenuates lung injury and prevents mortality in adult mice exposed to greater than 95% O 2 . Adult wild-type mice demonstrated evidence of alveolar protein leak and 100% mortality by 6 days of hyperoxic exposure, and showed NF-kB nuclear translocation that terminated after 48 hours. Furthermore, these mice showed increased expression of NF-kB-regulated proinflammatory and proapoptotic cytokines. In contrast, mice overexpressing the NF-kB inhibitory protein, IkBb (AKBI), demonstrated significant resistance to hyperoxic lung injury, with 50% surviving through 8 days of exposure. This was associated with NF-kB nuclear translocation that persisted through 96 hours of exposure. Although induction of NFkB-regulated proinflammatory cytokines was not different between wild-type and AKBI mice, significant up-regulation of antiapoptotic proteins (BCL-2, BCL-XL) was found exclusively in AKBI mice. We conclude that sustained NF-kB activity mediated by IkBb protects against hyperoxic lung injury through increased expression of antiapoptotic genes.Keywords: NF-kB; IkB; hyperoxic lung injury; apoptosis; inflammation Clinical RelevanceOxygen therapy is commonly employed in an attempt to improve oxygen delivery, and yet prolonged exposure results in lung injury. No pharmacologic strategies to attenuate hyperoxic lung injury have been identified. We show that enhancing hyperoxia-induced NF-kB activity attenuates lung injury, and thus represents a potential therapeutic target.The first studies demonstrating the lethal effect of inspiring high concentrations of oxygen were published over a century ago (1). Due to this toxicity, hyperoxic exposure has been widely used in animal studies to induce and study acute lung injury (2). Despite this, no pharmacologic therapies to attenuate hyperoxic lung injury have been identified.Hyperoxia induces proinflammatory cytokine expression (3), and results in pulmonary endothelial and epithelial cell death (4). Given these facts, both antiinflammatory and antiapoptotic strategies have been employed to attenuate hyperoxic lung injury. Although anti-inflammatory interventions have met variable success (5-9), increasing the expression of antiapoptotic factors in transgenic murine models results in attenuated hyperoxic lung injury (10-12). These studies suggest that preventing hyperoxia-induced apoptosis can prevent lung injury, but the transcriptional mechanism mediating expression of these factors is largely unknown.Hyperoxia-induced NF-kB activation has been documented in both pulmonary epithelial and endothelial cells (13). Whether this response is protective or injurious is unclear. Some in vivo s...

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Section: Discussionmentioning

confidence: 99%

IκBβ-Mediated NF-κB Activation Confers Protection against Hyperoxic Lung Injury

Michaelis

Agboke

Liu

et al. 2014

Am J Respir Cell Mol Biol

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“…Under cytotoxic conditions, certain cell types are needed for survival of the organism. In this case NF-κB, by increasing expression of several cohorts of metabolic enzymes and key hormones, can balance stress signals, and thereby protects essential cells [11,14,22,23]. NF-κB target genes consequently include cytokines, adhesion molecules, and specialized functional units of immune cells, as well as antiapoptotic proteins like Bcl-2 and Bfl-1, [13,24-26].…”

Section: Interactions Between Diverse Cell Types Shape Tissue Funcmentioning

confidence: 99%

“…In contrast, in tumor cells, under certain conditions, NF-κB mediates propagation of cell clones that have lost a key feedback inhibiting mechanism (Fig 2B); the result is cancer [14,15,38]. Malignant cells may respond to a lethal stimulus through a signal pathway that is disproportionately activated (Fig 1B), and has a critical influence on downstream enzymes [14,22], as we discuss in section (6).…”

Section: Interactions Between Diverse Cell Types Shape Tissue Funcmentioning

confidence: 99%

Dynamic aberrant NF-κB spurs tumorigenesis: A new model encompassing the microenvironment

Vlahopoulos¹,

Çen²,

Hengen³

et al. 2015

Cytokine & Growth Factor Reviews

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Recently it was discovered that a transient activation of transcription factor NF-κB can give cells properties essential for invasiveness and cancer initiating potential. In contrast, most oncogenes to date were characterized on the basis of mutations or by their constitutive overexpression. Study of NF-κB actually leads to a far more dynamic perspective on cancer: tumors caused by diverse oncogenes apparently evolve into cancer after loss of feedback regulation for NF-κB. This event alters the cellular phenotype and the expression of hormonal mediators, modifying signals between diverse cell types in a tissue. The result is a disruption of stem cell hierarchy in the tissue, and pervasive changes in the microenvironment and immune response to the malignant cells.

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“…In contrast, IB␤ has no nuclear export sequence and, once in the nucleus, acts to stabilize NF-B DNA binding and potentiate NF-B activity and downstream gene expression (47). This sustained NF-B activity protects cells from oxidant stress-induced cell death and prevents pulmonary oxygen toxicity in adult mice (44,58).…”

mentioning

confidence: 90%

Sustained hyperoxia-induced NF-κB activation improves survival and preserves lung development in neonatal mice

McKenna

Michaelis

Agboke

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Oxygen toxicity contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). Neonatal mice exposed to hyperoxia develop a simplified lung structure that resembles BPD. Sustained activation of the transcription factor NF-κB and increased expression of protective target genes attenuate hyperoxia-induced mortality in adults. However, the effect of enhancing hyperoxia-induced NF-κB activity on lung injury and development in neonatal animals is unknown. We performed this study to determine whether sustained NF-κB activation, mediated through IκBβ overexpression, preserves lung development in neonatal animals exposed to hyperoxia. Newborn wild-type (WT) and IκBβ-overexpressing (AKBI) mice were exposed to hyperoxia (>95%) or room air from day of life (DOL) 0-14, after which all animals were kept in room air. Survival curves were generated through DOL 14. Lung development was assessed using radial alveolar count (RAC) and mean linear intercept (MLI) at DOL 3 and 28 and pulmonary vessel density at DOL 28. Lung tissue was collected, and NF-κB activity was assessed using Western blot for IκB degradation and NF-κB nuclear translocation. WT mice demonstrated 80% mortality through 14 days of exposure. In contrast, AKBI mice demonstrated 60% survival. Decreased RAC, increased MLI, and pulmonary vessel density caused by hyperoxia in WT mice were significantly attenuated in AKBI mice. These findings were associated with early and sustained NF-κB activation and expression of cytoprotective target genes, including vascular endothelial growth factor receptor 2. We conclude that sustained hyperoxia-induced NF-κB activation improves neonatal survival and preserves lung development. Potentiating early NF-κB activity after hyperoxic exposure may represent a therapeutic intervention to prevent BPD.

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Nuclear Factor-κB (NF-κB) Inhibitory Protein IκBβ Determines Apoptotic Cell Death following Exposure to Oxidative Stress

Cited by 24 publications

References 32 publications

IκBβ-Mediated NF-κB Activation Confers Protection against Hyperoxic Lung Injury

IκBβ-Mediated NF-κB Activation Confers Protection against Hyperoxic Lung Injury

Dynamic aberrant NF-κB spurs tumorigenesis: A new model encompassing the microenvironment

Sustained hyperoxia-induced NF-κB activation improves survival and preserves lung development in neonatal mice

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