A Small Molecule Inhibitor of Redox-Regulated NF-κB and Activator Protein-1 Transcription Blocks Allergic Airway Inflammation in a Mouse Asthma Model

Henderson, William R.; Emil, Y.; Teo, Jia Ling; Nguyen, Cu; Kahn, Michaël

doi:10.4049/jimmunol.169.9.5294

Cited by 103 publications

(68 citation statements)

References 54 publications

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“…In contrast, MUC-5a/c activation could be regulated by both Src-and epidermal growth factor receptor-kinase dependent pathways involving NF-B signaling (54). As others treatments related to the NF-B inhibition in the airways demonstrated also a downregulatory effect on OVA-induced mucus production (27,28) through down-regulation of IL-13, our NF-B inhibition strategies failed to do so most probably because they did not interfere with tg expression. Levels of BAL IL-13 were not affected by these treatments.…”

Section: Discussionmentioning

confidence: 74%

“…It is also based on studies that demonstrated that the NF-B pathway plays an essential role in the induction of airway eosinophilic inflammation (22) and regulation of Th2 cytokine production by interfering with GATA-3 expression (23). Indeed, a variety of interventions that inhibit NF-B activation including the administration of p65 antisense oligonucleotides (24), NF-B decoy nucleotides (25), small molecule inhibitors of both NF-B and AP-1 (26,27), and IB superrepressor constructs (CC10-IB␣ SR -transgenic (tg) mice) (28) have all been shown to inhibit aspects of the experimental asthmatic response. Exaggerated NF-B signaling has also been implicated in the pathogenesis of COPD (29,30).…”

Section: Inhibition Of Nf-b Activation Reduces the Tissue Effects Of mentioning

confidence: 99%

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Inhibition of NF-κB Activation Reduces the Tissue Effects of Transgenic IL-13

Chapoval

Al-Garawi²,

Lora³

et al. 2007

The Journal of Immunology

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IL-13 is a major Th2 cytokine that is capable of inducing inflammation, excessive mucus production, airway hyperresponsiveness, alveolar remodeling, and fibrosis in the murine lung. Although IL-13 through its binding to IL-4Rα/IL-13Rα1 uses the canonical STAT6-signaling pathway to mediate these tissue responses, recent studies have demonstrated that other signaling pathways may also be involved. Previous studies from our laboratory demonstrated that IL-13 mediates its tissue effects by inducing a wide variety of downstream genes many of which are known to be regulated by NF-κB. As a result, we hypothesized that NF-κB activation plays a critical role in the pathogenesis of IL-13-induced tissue alterations. To test this hypothesis, we compared the effects of transgenic IL-13 in mice with normal and diminished levels of NF-κB activity. Three pharmacologic approaches were used to inhibit NF-κB including 1) PS1145, a small molecule inhibitor of IκBα kinase (IKK2), 2) antennapedia-linked NF-κB essential modulator-binding domain (NBD) peptide (wild-type NBD), and 3) an adenoviral construct expressing a dominant-negative version of IKK2. We also crossed IL-13-transgenic mice with mice with null mutations of p50 to generate mice that overproduced IL-13 in the presence and absence of this NF-κB component. These studies demonstrate that all these interventions reduced IL-13-induced tissue inflammation, fibrosis and alveolar remodeling. In addition, we show that both PS1145 and wild-type NBD inhibit lung inflammatory and structural cell apoptosis. PS1145 inhibits caspase activation and up-regulates inhibitor of apoptosis protein cellular-inhibitor of apoptosis protein 1 (c-IAP-1). Therefore, NF-κB is an attractive target for immunotherapy of IL-13-mediated diseases.

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Section: Discussionmentioning

confidence: 74%

Section: Inhibition Of Nf-b Activation Reduces the Tissue Effects Of mentioning

confidence: 99%

Inhibition of NF-κB Activation Reduces the Tissue Effects of Transgenic IL-13

Chapoval

Al-Garawi²,

Lora³

et al. 2007

The Journal of Immunology

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“…Moreover, oxidative stress induces an increase in the peroxidation of lipids, proteins, and DNA, as well as the production of chemoattractants, as well as enhancing AHR, airway secretion, and vascular permeability in asthmatic airways (Barnes et al, 1990;Henricks et al, 2001;Andreadis et al, 2003). ROS also promotes the activities of proinflammatory redox-sensitive nuclear factors, including NF-κB, thus increasing the allergic inflammation observed in asthmatic patients (Henderson et al, 2002;Rahman et al, 2003). These results show that ROS may perform essential functions for both the induction of airway inflammation and for the pathogenesis of asthmatic diseases.…”

Section: Discussionmentioning

confidence: 99%

Regulation of pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen species in vitro and in vivo

Kim

Moon

et al. 2008

Exp Mol Med

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Reactive oxygen species (ROS) performs a pivotal function as a signaling mediator in receptor-mediated signaling. However, the sources of ROS in this signaling have yet to be determined, but may include lipoxygenases (LOXs) and NADPH oxidase. The stimulation of lymphoid cells with TNF-α, IL-1β, and LPS resulted in significant ROS production and NF-κB activation. Intriguingly, these responses were markedly abolished via treatment with the LOXs inhibitor nordihydroguaiaretic acid (NDGA). We further examined in vivo anti-inflammatory effects of NDGA in allergic airway inflammation. Both intraperitoneal and intravenous NDGA administration attenuated ovalbumin (OVA)-induced influx into the lungs of total leukocytes, as well as IL-4, IL-5, IL-13, and TNF-α levels. NDGA also significantly reduced serum levels of OVA-specific IgE and suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. The results of our histological studies and flow cytometric analyses showed that NDGA inhibits OVA-induced lung inflammation and the infiltration of CD11b + macrophages into the lung. Collectively, our findings indicate that LOXs performs an essential function in pro-inflammatory signaling via the regulation of ROS regulation, and also that the inhibition of LOXs activity may have therapeutic potential with regard to the treatment of allergic airway inflammation.

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“…Development of oxidant/antioxidant imbalance in asthma leads to activation of redox-sensitive transcription factor NF-κB (Henderson et al, 2002). ROS have also been directly implicated as second messengers in the activation of NF-κB, based upon the ability of oxidants to activate NF-κB by the oxidation of its cysteine-SH group or by ubiquitination and proteolysis of IκB (Ginn-Pease and Whisler, 1996;Shang et al, 1997;Rahman and MacNee, 1998).…”

Section: Discussionmentioning

confidence: 99%

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

Lee

Kim²,

Park³

et al. 2007

Exp Mol Med

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Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-κB and hypoxia-inducible factor-1α (HIF-1α ) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-κB and HIF-1α as well as reducing ROS generation in allergic airway disease.

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A Small Molecule Inhibitor of Redox-Regulated NF-κB and Activator Protein-1 Transcription Blocks Allergic Airway Inflammation in a Mouse Asthma Model

Cited by 103 publications

References 54 publications

Inhibition of NF-κB Activation Reduces the Tissue Effects of Transgenic IL-13

Inhibition of NF-κB Activation Reduces the Tissue Effects of Transgenic IL-13

Regulation of pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen species in vitro and in vivo

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

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