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Aims Glucocorticoids are the most effective anti-inflammatory agent in treating pulmonary diseases typically accompanied by hypoxia. Our previous study has demonstrated that glucocorticoid receptor α (GRα) expression is reduced in hypoxia but the underlying mechanism remains elusive. In this study we aim to identify the signaling pathway involved in hypoxia-induced down-regulation of GRα, and whether hypoxia affects nuclear translocation of GRα. Main methods Female C57BL/6 mice were sensitized with saline or ovalbumin (OVA) as the in vivo model. Mice were divided into control and OVA groups, and their lung histology and the expression of hypoxia inducible factor (HIF-1) and GRα were examined. A549 cells were exposed to chemical hypoxia as the in vitro model, where mitogen-activated protein kinases (MAPKs) were inhibited specifically by SB203580. Next, under normal or hypoxic conditions, the expression of GRα, MAPKs and HIF-1 signal protein were determined by Western blot analysis, and GRα translocation were observed through live-cell imaging. Key findings In OVA challenged mice the expression of GRα was down-regulated whereas HIF-1 was up-regulated. Hypoxia caused a time-dependent decrease of GRα expression, and activated multiple signaling pathways including MAPKs and HIF-1. Moreover, GRα expression increased with MAPK inhibition. Interestingly, only MAPK inhibitor SB203580, but not JNK inhibitor SP600125 or ERK inhibitor U0126 improved the expression of GRα under hypoxic condition. GRα nuclear translocation was also significantly inhibited by hypoxia. Significance Hypoxia down-regulated the expression of GRα through p38 signaling pathway, as well as inhibited GRα nuclear translocation significantly. [ABSTRACT FROM AUTHOR]

Numerous studies indicate that toll-like receptor 2 (TLR2) led to divergent effects in asthma. The occurrence of autophagy in asthma pathogenesis is still incompletely understood. Here, we aimed to investigate the role of TLR2 and the underlying mechanisms in allergic airway inflammation and autophagy activation. C57BL/6 and TLR2 knockout (TLR2−/−) mice were subjected to an ovalbumin (OVA)-immunized allergic airway model, and were treated with SP600125. Differential cell counts in bronchoalveolar lavage fluid were determined by Wright's staining. Histological analysis of airway inflammation was determined by haematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. The levels of OVA-specific immunoglobulin E (IgE), tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) were detected by enzyme-linked immunosorbent assay (ELISA). Proteins expression in lung tissues was detected by western blot, expression of TLR2 was further observed by immunofluorescence. Autophagy activation was determined by western blot and transmission electron microscopy (TEM). TLR2 expression was increased upon OVA challenge, and TLR2 deficiency was associated with decreased allergic airway inflammation. Meanwhile, TLR2 deficiency weakened autophagy activation. Moreover, inhibition of c-Jun N-terminal kinase (JNK) by SP600125 also suppressed OVA-induced allergic airway inflammation and autophagy activation. Interestingly, treating TLR2−/− mice with SP600125 showed similar OVA-induced allergic airway inflammation and autophagy activation compared to that in vehicle-treated TLR2−/− mice. TLR2 might contribute to the maintenance of allergic airway inflammation through JNK signaling pathway accompanying with autophagy activation. These findings may provide a novel signal target for prevention of allergic airway inflammation. [ABSTRACT FROM AUTHOR]