Interleukin-37 alleviates airway inflammation and remodeling in asthma via inhibiting the activation of NF-κB and STAT3 signalings.

Asthma is a common respiratory inflammatory disorder disease of childhood, and airway smooth muscle cells (ASMCs) play an important role in this disease. Recently, studies have found that interleukin (IL)-37 inhibits allergic airway inflammation of asthmatic mouse models. The aim of this study was to investigate the exact mechanism of IL-37 in asthma. In this study, we found recombinant human IL-37 protein significantly reduced ovalbumin (OVA)-induced airway hyperresponsiveness, inflammatory cell infiltration, the epithelial-mesenchymal-transition (EMT) process, and levels of IL-4, IL-6 and IL-13, but increased interferon (IFN)-γ expression. Moreover, IL-37 treatment remarkably inhibited transforming growth factor (TGF)-β1-induced cell proliferation, migration, EMT, and inflammatory response in ASMCs. IL-37 notably upregulated IκB expression and downregulated levels of NF-κB p65, phospho-NF-κB p65, STAT3 and phospho-STAT3 both in OVA-induced mice and in TGF-β1-stimulated ASMCs. The effects of IL-37 on TGF-β1-induced ASMCs were abrogated by STAT3 upregulation. Additionally, PDTC, a NF-κB inhibitor, showed the similar effects as IL-37 in ASMCs. In conclusion, IL-37 may alleviate airway inflammation and remodeling in asthma through suppressing the activation of NF-κB and STAT3.

Huang N ，Liu K ，Liu J ，Gao X ，Zeng Z ，Zhang Y ，Chen J ... -  《-》

Icariside II attenuates eosinophils-induced airway inflammation and remodeling via inactivation of NF-κB and STAT3 in an asthma mouse model.

Asthma is a chronic inflammatory airway disease. Icariside II has been reported to exert anti-inflammatory effect in multiple human diseases. The present study aimed to investigate the effects and mechanisms of Icariside II on airway inflammation and remodeling in asthma. We established an asthma mouse model with ovalbumin (OVA) immunization. Histological analysis using H&E, PAS and Masson staining showed that administration of Icariside II attenuated OVA-induced airway inflammation and remodeling. Icariside II reduced the numbers of total white blood cells and eosinophils in bronchoalveolar lavage fluid (BALF). The levels of interleukin (IL)-4, IL-5, IL-13 and transforming growth factor (TGF)-β1 in peripheral blood and the expression of α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), eotaxin-1, CC-chemokine receptor-3 (CCR-3), Toll-like receptor (TLR)-2 and TLR-4 were significantly down-regulated in lung tissues of OVA-induced mouse model. These results suggested that Icariside II inhibited eosinophil activation and thus decreased eosinophils-induced airway inflammation and remodeling in asthma. Moreover, Icariside II suppressed TGF-β1-induced cell proliferation, migration, and CTGF expression in airway smooth muscle cells (ASMCs). In both OVA-induced mouse model of asthma and TGF-β1-induced ASMCs, Icariside II decreased IκBα degradation, nuclear translocation of NF-κB p65 and STAT3 phophorylation, indicating an inactivation of NF-κB and STAT3 in the presence of Icariside II. Therefore, we demonstrate that Icariside II attenuates eosinophils-induced airway inflammation and remodeling in asthmatic mice and inhibits TGF-β1-induced cell proliferation and migration in ASMCs via suppressing NF-κB and STAT3 signalings.

Tian C ，Gao F ，Li X ，Li Z ... -  《-》

Targeted inhibition of GATA-6 attenuates airway inflammation and remodeling by regulating caveolin-1 through TLR2/MyD88/NF-κB in murine model of asthma.

The purpose of this study was to evaluate the effects of GATA-6 on airway inflammation and remodeling and the underlying mechanisms in a murine model of chronic asthma. Female BALB/c mice were randomly divided into four groups: phosphate-buffered saline control (PBS), ovalbumin (OVA)-induced asthma group (OVA), OVA+ siNC and OVA+ siGATA-6. In this mice model, GATA-6 expression level was significantly elevated and the expression in Caveolin-1 (Cav-1) inversely correlated with the abundance of GATA-6 in OVA-induced asthma of mice. Silencing of GATA-6 gene expression upregulated Cav-1 expression. Additionally, downregulation of GATA-6 dramatically decreased OVA-challenged inflammation, infiltration, and mucus production. Moreover, silencing of GATA-6 resulted in decreased levels of immunoglobulin E (IgE) and inflammatory mediators and reduced inflammatory cell accumulation, as well as inhibiting the expression of important mediators including matrix metalloproteinase (MMP)-2 and MMP-9, TGF-β1, and a disintegrin and metalloproteinase 8 (ADAM8) and ADAM33, which is related to airway remodeling. Further analysis confirmed that silencing of GATA-6 attenuated OVA-induced airway inflammation and remodeling through the TLR2/MyD88 and NF-κB pathway. In conclusion, these findings indicated that the downregulation of GATA-6 effectively inhibited airway inflammation and reversed airway remodeling via Cav-1, at least in part through downregulation of TLR2/MyD88/NF-κB, which suggests that GATA-6 represents a promising therapeutic strategy for human allergic asthma.

Fang P ，Shi HY ，Wu XM ，Zhang YH ，Zhong YJ ，Deng WJ ，Zhang YP ，Xie M ... -  《-》

Saikosaponin A ameliorates nasal inflammation by suppressing IL-6/ROR-γt/STAT3/IL-17/NF-κB pathway in OVA-induced allergic rhinitis.

Allergic rhinitis (AR) is a type I hypersensitivity immune response and is a common chronic allergic respiratory disorder characterized by one or more nasal symptoms. Despite many studies on AR therapy, the drugs of treatment for AR remain limited in effect. In the present study, we aimed to elucidate the effects of saikosaponin A (SSA) on nasal inflammation, T helper (Th)2 and Th17 cytokines, retinoic acid-related orphan nuclear receptor (ROR)-γt, signal transducer and activator of transcription (STAT)3, and nuclear factor (NF)-κB signalings in ovalbumin (OVA)-induced AR mice model. OVA-induced AR mice exhibited increase in nasal symptoms, histological alteration, OVA-specific immunoglobulin (Ig)E/IgG1, ROR-γt, STAT3 and NF-κB signalings. However, the administration of SSA significantly decreased allergic symptoms including nasal rubbing and sneezing. Additionally, histological alterations such as mucosa layer thickness, goblet cell hyperplasia, eosinophils and mast cell infiltration in nasal tissues dramatically improved by treatment with SSA. Also, SSA treatment decreased the levels of OVA-specific IgE/IgG1 in serum and the levels of Th2 and Th17 cytokines such as interleukin (IL)-6 and IL-17 in nasal lavage fluid (NALF). Moreover, SSA inhibited the activation of transcription factor ROR-γt, STAT3 and phosphorylated STAT3 in both NALF and lung. Futher, SSA could also significantly inhibit the expressions of NF-κB p65 and phosphorylated NF-κB p65 in NALF and lung. These present results suggested that SSA may attenuate OVA-induced allergic rhinitis through regulating the expression of IL-6/ROR-γt/STAT3/IL-17/NF-κB signaling. The results indicate that SSA may be used as a therapeutic candidate for allergic rhinitis disease.

Piao CH ，Song CH ，Lee EJ ，Chai OH ... -  《-》

Shikonin alleviates allergic airway remodeling by inhibiting the ERK-NF-κB signaling pathway.

Shikonin is a naphthoquinone extracted from the root of Lithospermum erythrorhizon, and has been reported to suppress allergic airway inflammation in mice. However, the underlying mechanisms are unclear and need to be further elucidated. In this study, shikonin (0.5, 2 or 4mg/kg) was given intraperitoneally to ovalbumin (OVA)-challenged BALB/c mice. We found that the pathological airway remodeling of asthmatic mice was alleviated by shikonin, and the infiltrated inflammatory cells and collagen deposition in their lungs were reduced. Furthermore, the abnormal activation of extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) pathway and the elevation of matrix metalloproteinase 9 (MMP9) in the lung of asthmatic mice were suppressed by shikonin. The inactivation of NF-κB by shikonin was at least in part via inhibiting IκBα activation. In vitro, the treatment of shikonin inhibited the platelet-derived growth factor (PDGF)-induced proliferation of primary airway smooth muscle cells (ASMCs), and induced a G0/G1 arrest in these cells. In addition, ASMCs exposed to PDGF acquired an enhanced migratory ability, and the activities of MMP9 and matrix metalloproteinase 2 (MMP2) and expression of MMP9 of these cells were significantly up-regulated. These PDGF-induced alterations were also inhibited by shikonin. The inhibitory effects of shikonin on the proliferation and migration of ASMCs were comparable to pyrrolidinedithiocarbamate (PDTC), an inhibitor of NF-κB pathway. In conclusion, the present study sheds lights on how shikonin alleviates allergic airway remodeling.

Wang TY ，Zhou QL ，Li M ，Shang YX ... -  《-》