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.

Otorhinolaryngology Institute of Sun Yat-Sen University, Guangzhou, China.
ORL (Impact Factor: 1.1). 01/2010; 72(5):256-65. DOI: 10.1159/000312687
Source: PubMed

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.

  • [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 01/2014; 2014:829068. · 3.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anaplastic large-cell lymphomas (ALCLs) bearing the t(2;5) translocation (ALK(+)ALCLs) are frequently characterized by skin colonization and associated with a poor prognosis. Using conditional transgenic models of anaplastic lymphoma kinase-positive (ALK(+)) lymphomas and human ALK(+)ALCL cell lines, in the present study, we show that high-mobility-group box-1 (HMGB-1), a proinflammatory cytokine, is released by ALK(+) cells, and demonstrate extracellular HMGB-1-stimulated secretion of the IL-8 chemokine by HaCaT keratinocytes through the involvement of MMP-9, PAR-2, and the NF-κB pathway. Furthermore, we demonstrate that, in vitro, IL-8 is able to induce the invasiveness of ALK(+) cells, which express the IL-8 receptors CXCR1 and CXCR2. In vitro and in vivo, HMGB-1 inhibition achieved by glycyrrhizin treatment led to a drastic reduction in ALK(+) cell invasiveness. The pathophysiological relevance of our observations was confirmed by demonstrating that the HMGB-1 and IL-8 receptors are expressed in ALK(+)ALCL biopsies. We have also shown that IL-8 secretion is correlated with leukemic dissemination of ALK(+) cells in a significant number of patients. The results of the present study demonstrate for the first time a relationship among the pro-inflammatory mediators HMGB-1, MMP-9, PAR-2, and IL-8. We propose that these mediators create a premetastatic niche within the skin, thereby participating in ALK(+) lymphoma epidermotropism.
    Blood 03/2012; 119(20):4698-707. · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Severe asthma is associated with T helper (T H) 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. Objective: To determine the anti-inflammatory potential of anthraquinones in-vivo. Methods: 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. Results: 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 T H 2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung. Conclusion: 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. Copyright: © 2013 Cesar de Souza Alves et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    PLoS ONE 11/2013; · 3.53 Impact Factor