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/NFκB Signaling

Otorhinolaryngology Institute of Sun Yat-Sen University, Guangzhou, China.
ORL (Impact Factor: 0.88). 09/2010; 72(5):256-65. DOI: 10.1159/000312687
Source: PubMed


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.

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    • "The PI3K/AKT signaling pathway is also activated by HDM allergen Der p1 binding to protease-activated receptors [64] and LPS (e.g. in crude HDM extract) sensing by TLR4 [65]. Thus employing non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of both allergen- and RV-triggered severe asthma (Figure 7). "
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    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 · 3.23 Impact Factor
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    • "However, it is interesting to note that PAR-1 and PAR-2 expression was upregulated in primary human nasal epithelial cells incubated with Der p 1 and that Der p 1 stimulated a PAR-2-dependent downregulation of connexin, a protein involved in the integrity of tight junctions [111, 112]. "
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    ABSTRACT: Sensitizations to house dust mites (HDM) trigger strong exacerbated allergen-induced inflammation of the skin and airways mucosa from atopic subjects resulting in atopic dermatitis as well as allergic rhinitis and asthma. Initially, the Th2-biased HDM allergic response was considered to be mediated only by allergen B- and T-cell epitopes to promote allergen-specific IgE production as well as IL-4, IL-5, and IL-13 to recruit inflammatory cells. But this general molecular model of HDM allergenicity must be revisited as a growing literature suggests that stimulations of innate immune activation pathways by HDM allergens offer new answers to the following question: what makes an HDM allergen an allergen? Indeed, HDM is a carrier not only for allergenic proteins but also microbial adjuvant compounds, both of which are able to stimulate innate signaling pathways leading to allergy. This paper will describe the multiple ways used by HDM allergens together with microbial compounds to control the initiation of the allergic response through engagement of innate immunity.
    02/2013; 2013(4):735031. DOI:10.1155/2013/735031
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