Glucocorticoids Modulate Th1 and Th2 Responses in Asthmatic Mouse Models by Inhibition of Notch1 Signaling

Abstract

Background: Notch1 has been linked to the pathogenesis of asthma due to its contribution on Th1/Th2 imbalance. γ-Secretase inhibitor (GSI) acts as an effective blocker of Notch1 signaling. Glucocorticoids (GCs) are the most effective anti-inflammatory drugs for asthma. The present study investigated the involvement of the Notch1 pathway in the anti-inflammatory effect of GCs and its association with Th1/Th2 balance. Methods: The asthma model was established in BALB/c mice by sensitization with ovalbumin (OVA). Dexamethasone (DEX; 1 mg/kg) and/or GSI (0.03 mg/kg) was orally or intranasally administrated. Results: Compared to the OVA-sensitized mice, the administration of DEX and/or GSI significantly ameliorated the airway inflammation infiltration, goblet cell metaplasia, and airway hyper-responsiveness. The expression of IL-4 and IL-13, as well as the ratios of eosinophils and lymphocytes, were significantly decreased, whereas IFN-γ and IL-2 levels were significantly increased in bronchoalveolar lavage fluid after the administration of DEX and GSI. The expressions of the Notch1/NICD1 pathway were decreased after DEX and/or GSI administration in lung tissues, especially in CD4+ T cells. Also, a reduction of GATA3 and elevation of T-bet levels were correlated with the upregulation of Th1/Th2 ratios in lung tissues. Conclusions: Through the inhibition of Notch1 signaling, both GSI and GCs could regulate Th1/Th2 balance involved in allergic airway inflammation in OVA-induced asthma.

miR-30a-3p participates in the development of asthma by targeting CCR3

“…Increasing evidence has indicated that the incidence and mortality rates of asthma have markedly increased worldwide. It has been reported that glucocorticoid drugs exhibit protective effects on airway remodeling and inflammation in a mouse asthma model [32][33][34].…”

Recent Advances in Experimental Allergy

“…Hu et al [26] investigated the role of Notch1 signaling as well as therapeutic capabilities of a γ-secretase inhibitor (GSI), which inhibits Notch 1. Notch 1 is thought to contribute to the development of asthma by contributing to the Th1/Th2 disbalance [27].…”

“…DEX and/or GSI treatment reduced the expression of the Notch1/NICD1 pathway in the lung, particularly in CD4 + T cells. Evidence of the upregulation of Th1/Th2 ratios in lung tissues, via a reduction in GATA3 and an increase in T-bet, was observed [26]. …”

Bronchial Epithelial Cells Promote the Differentiation of Th2 Lymphocytes in Airway Microenvironment through Jagged/Notch-1 Signaling after RSV Infection

“…The Notch signaling pathway is a highly evolutionarily conserved cell signaling pathway in most multicellular organisms that regulates proliferation, differentiation, cell fate, progenitor, and stem-cell self-renewal in both embryonic and adult tissues. Reports indicate that it is involved in AHR [9]. Several studies have demonstrated that BECs can express all the ligands of Notch-1, which is correlated with the differentiation of Th lymphocytes [10].…”