Induction of IL-6 and IL-8 by house dust mite allergen Der p1 in cultured human nasal epithelial cells is associated with PAR/PI3K/NFkappaB signaling.
ABSTRACT The mechanism of action involved in how Dermatophagoides pteronyssinus (Der p) 1 initiates the nasal allergic cascade is poorly understood.
We detected proinflammatory cytokine production (GM-CSF, TNF-α, IL-1β, IL-6, and IL-8) and associated signal molecules in primarily cultured nasal epithelial cells (NECs) from patients with allergic rhinitis (AR) after Der p1 stimulation, using ELISA, RT-PCR, and Western blot. We also evaluated the importance of protease-activated receptors (PAR)/phosphatidylinositol 3 kinase (PI3K)/NFκB signaling pathways in IL-6 and IL-8 production using glucocorticoids and specific inhibitors, LY294002 and PDTC.
We observed significantly elevated IL-6 and IL-8 production (both gene and protein) in NECs after Der p1 stimulation, and demonstrated that the expressions of PAR2, pAkt, and pp65 were upregulated after Der p1 stimulation, which were associated with IL-6 and IL-8 production in NECs.
These findings demonstrate that the PAR/PI3K/NFκB signaling pathway is involved in the induction of IL-6 and IL-8 in Der-p1-stimulated NECs from AR patients, and may have potential implications for the prevention and treatment of AR and asthma.
SourceAvailable from: Caio Cesar Souza Alves[Show abstract] [Hide abstract]
ABSTRACT: Severe asthma is associated with T helper (TH) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro. To determine the anti-inflammatory potential of anthraquinones in-vivo. BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation. Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of TH2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung. Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.PLoS ONE 11/2013; 8(11):e79565. DOI:10.1371/journal.pone.0079565 · 3.53 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Allergic rhinitis (AR) is a common chronic inflammatory condition of the nasal mucosal tissue. The interleukin-13 (IL-13) signaling pathway is of great importance in the pathogenesis of AR. However, how the signaling molecules in this pathway are regulated, particularly through microRNAs (miRNAs), remains unclear. In the present study, we investigated the regulatory role and mechanism of miRNA-143 (miR-143) in IL-13-induced inflammatory cytokine and mucus production in nasal epithelial cells (NECs) from AR patients. Our results showed that forced expression of miR-143 significantly decreased the mRNA and protein expression levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), eotaxin and mucin 5AC (MUC5AC) in IL-13-stimulated NECs. Moreover, we confirmed that miR-143 directly targeted and significantly suppressed IL-13 receptor α1 chain (IL13Rα1) gene expression. This study thus suggests that miR-143 regulation of IL-13-induced inflammatory cytokine and mucus production in NECs from AR patients probably partly depends on inhibition of IL13Rα1. Therefore, the IL13Rα1 signaling pathway may be a potential target for the prevention and treatment of AR by miR-143. Copyright © 2014. Published by Elsevier Inc.Biochemical and Biophysical Research Communications 12/2014; 457(1). DOI:10.1016/j.bbrc.2014.12.058 · 2.28 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Protease activated receptors (PARs) have been recognized as a distinctive four-member family of seven transmembrane G protein-coupled receptors (GPCRs) that can be cleaved by certain serine proteases. In recent years, there has been considerable interest in the role of PARs in allergic inflammation, the fundamental pathologic changes of allergy, but the potential roles of PARs in allergy remain obscure. Since many of these proteases are produced and actively involved in the pathologic process of inflammation including exudation of plasma components, inflammatory cell infiltration, and tissue damage and repair, PARs appear to make important contribution to allergy. The aim of the present review is to summarize the expression of PARs in inflammatory and structural cells, the influence of agonists or antagonists of PARs on cell behavior, and the involvement of PARs in allergic disorders, which will help us to better understand the roles of serine proteases and PARs in allergy.Mediators of Inflammation 04/2014; 2014:829068. DOI:10.1155/2014/829068 · 2.42 Impact Factor