Abstract
BackgroundOveractivation of nuclear factor κB (NF-κB) orchestrates airway eosinophilia, but does not dampen airway hyperresponsiveness in asthma. NF-κB repression by arsenic trioxide (As2O3) contributes to apoptosis of eosinophils (EOS) in airways. Here we provide evidence that As2O3 abrogates allergen (OVA)-induced airway eosinophilia by modulating the expression of IκBα, an NF-κB inhibitory protein, and decreases the airway hyperresponsiveness.MethodsUsing a murine model of asthma, the airway hyperresponsiveness was conducted by barometric whole-body plethysmography. Airway eosinophilia, OVA-specific IgE in serum, and chemokine eotaxin and RANTES (regulated upon activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid were measured by lung histology, Diff-Quick staining, and ELISA. Chemokine-induced EOS chemotactic activity was evaluated using EOS chemotaxis assay. Electrophoretic mobility shift assay and Western blot analysis were performed to assess pulmonary NF-κB activation and IκBα expression, respectively.ResultsAs2O3 attenuated the allergen-induced serum IgE, chemokine expression of eotaxin and RANTES, and the EOS recruitment in bronchoalveolar lavage fluid, which is associated with an increased IκBα expression as well as a decreased NF-κB activation. Also, As2O3 suppressed the chemotaxis of EOS dose-dependently in vitro. Additionally, As2O3 significantly ameliorated the allergen-driven airway hyperresponsiveness, the cardinal feature underlying asthma.ConclusionThese findings demonstrate an essential role of NF-κB in airway eosinophilia, and illustrate a potential dissociation between airway inflammation and hyperresponsiveness. As2O3 likely exerts its broad anti-inflammatory effects by suppression of NF-κB activation through augmentation of IκBα expression in asthma.
Highlights
Overactivation of nuclear factor κB (NF-κB) orchestrates airway eosinophilia, but does not dampen airway hyperresponsiveness in asthma
Histological analysis of the OVAchallenged mice lung revealed an enhanced airway eosinophilia as compared to the naïve control mice that were treated with phosphate-buffered saline (PBS) (Fig. 2A)
Examination of bronchoalveolar lavage fluid (BALF) collected from mice at 24 hrs after OVA challenge showed a marked influx of inflammatory cells into the airways, including EOS, lymphocytes, macrophages and neutrophils (Fig. 2B–C)
Summary
Overactivation of nuclear factor κB (NF-κB) orchestrates airway eosinophilia, but does not dampen airway hyperresponsiveness in asthma. We provide evidence that As2O3 abrogates allergen (OVA)-induced airway eosinophilia by modulating the expression of IκBα, an NF-κB inhibitory protein, and decreases the airway hyperresponsiveness. Asthma is accepted as a T-helper type 2 (Th2) lymphocyte-mediated chronic inflammatory disorder, characterized by airway eosinophilia and airway hyperresponsiveness (AHR) [1]. There is growing recognition that these processes involve increased transcription of inflammatory genes via transcription factors [4]. One such transcription factor, nuclear factor κB (NF-κB), is abundant of p50 (NF-κB1)/ p65 (RelA) heterodimer. The nuclear localization sequence of NF-κB is unmasked to allow its translocation into the nucleus, where it binds to DNA and initiates transcription of a wide range of NFκB-dependent genes in association with immune and inflammatory responses [7]
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