Abstract
The main purpose of this study was to investigate whether the blockade of the interaction between the receptor activator of nuclear factor-κB (NF-ĸB) ligand (RANKL) and its receptor RANK as well as the blockade of NF-κB inhibitor kinase (IKK) and of NF-κB translocation have the potential to suppress the pathogenesis of allergic asthma by inhibition and/or enhancement of the production by CD4+ and CD8+ T cells of important cytokines promoting (i.e., IL-4 and IL-17) and/or inhibiting (i.e., IL-10 and TGF-β), respectively, the development of allergic asthma. Studies using ovalbumin(OVA)-immunized mice have demonstrated that all the tested therapeutic strategies prevented the OVA-induced increase in the absolute number of IL-4- and IL-17-producing CD4+ T cells (i.e., Th2 and Th17 cells, respectively) indirectly, i.e., through the inhibition of the clonal expansion of these cells in the mediastinal lymph nodes. Additionally, the blockade of NF-κB translocation and RANKL/RANK interaction, but not IKK, prevented the OVA-induced increase in the percentage of IL-4-, IL-10- and IL-17-producing CD4+ T cells. These latter results strongly suggest that both therapeutic strategies can directly decrease IL-4 and IL-17 production by Th2 and Th17 cells, respectively. This action may constitute an important mechanism underlying the anti-asthmatic effect induced by the blockade of NF-κB translocation and of RANKL/RANK interaction. Thus, in this context, both these therapeutic strategies seem to have an advantage over the blockade of IKK. None of the tested therapeutic strategies increased both the absolute number and frequency of IL-10- and TGF-β-producing Treg cells, and hence they lacked the potential to inhibit the development of the disease via this mechanism.
Highlights
Glucocorticosteroids are still the mainstay of asthma therapy, they are not always sufficiently efficacious and their use can be associated with side effects
None of the tested therapeutic strategies increased both the absolute number and frequency of IL-10- and TGF-β-producing Treg cells, and they lacked the potential to inhibit the development of the disease via this mechanism
Immunization with OVA induced an increase in the percentage of IL-4, IL-10- and IL17-producing cells within non-Treg CD4+ T cells in the lungs (Figure 1B,E, Figure 2B,E, and Figure 3B,E, respectively)
Summary
Glucocorticosteroids are still the mainstay of asthma therapy, they are not always sufficiently efficacious and their use can be associated with side effects. Glucocorticoid insensitivity presents a profound management problem in patients with asthma because conventional therapies are not effective [1]. The treatment of patients with steroid-resistant asthma will require novel therapies tailored to this specific subgroup of patients. Researchers are looking for new targets for allergic asthma therapy. Nuclear factor-κB (NF-κB) is considered to be a promising target for the development of a novel therapeutic strategy in asthma treatment because allergic airway inflammation (AAI). Is mediated by the NF-κB pathway [2]. The down-regulation of this pathway may be an effective and rational approach for the treatment of allergic asthma
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