Abstract
Shp2 played an important role in cigarette-smoke-mediated inflammation, surfactant homeostasis and asthmatic airway remodeling. However, whether shp2 plays a key role in epithelium-associated allergic reaction is still unknown. In this study, LPS and OVA were observed to induce the production of IL-25 in bronchial epithelial cells in vitro via the activation of MAPK p38 and JNK. Furthermore, blockage of Shp2 by its specific inhibitor PHPS1 or by siRNA-mediated depletion was found to reduce the production of IL-25 in epithelial cells as well as the up-regulated LPS-triggered activation of JNK but not p38. To confirm the role of intra-bronchial epithelial Shp2 in OVA-induced allergic reaction, we generated CC10-rtTA/(tetO)7-Cre/Shp2f/f mice, where Shp2 was conditionally knocked out in bronchial epithelial cells. Surprisingly, specific deletion of Shp2 in bronchial epithelial cells showed a mild but insignificant effect on the expressions of epithelium-derived cytokines as well as TH2 and TH17 polarization following allergen-induced murine airway inflammation. Collectively, our data suggested that deletion of Shp2 impaired IL-25 production in bronchial epithelial cells in vitro, but might yet have minor influence on OVA-induced allergic reaction in vivo.
Highlights
Asthma is a T-lymphocyte-controlled disease of the airway that is characterized with airway inflammation, overproduction of mucus and airway wall remodeling, leading to bronchial hyperreactivity and airflow obstruction[1]
In Beas-2b cells, the level of IL-25 mRNA 48 hours after OVA treatment were significantly elevated in mouse tracheal epithelial cells (MTECs) (Fig 1B); in Beas-2b cells, the results showed that IL-25 could be triggered by OVA in a concentration-dependent manner (Fig 1C) as well as a time-dependent manner (Fig 1D)
Since OVA cannot be recognized by pattern recognition receptors (PRRs) on the epithelial membrane, we assumed that the contaminated LPS activated epithelium
Summary
Asthma is a T-lymphocyte-controlled disease of the airway that is characterized with airway inflammation, overproduction of mucus and airway wall remodeling, leading to bronchial hyperreactivity and airflow obstruction[1]. TLR4 triggering by LPS (Lipopolysacchatide) primes downstream cellular events, which are mediated by mitogen-activated protein kinase (MAPK) p38 and c-Jun Nterminal kinase (JNK), causing nuclear translocation of NF-κB. Lambrechts showed irradiated chimeric mice–in which Toll-like receptor 4 (TLR4) expressed on radio-resistant lung structural cells but not on dendritic cells (DCs)–were still primed type-2 responses to HDM (House dust mites). They documented that deficiency of TLR4 on structural cells other than on DCs still inhibited HDM-induced allergic airway inflammation[5]. These findings suggest airway epithelial cells are necessary in driving allergic inflammation in the early stage of the disease
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