Tangeretin has anti-asthmatic effects via regulating PI3K and Notch signaling and modulating Th1/Th2/Th17 cytokine balance in neonatal asthmatic mice.

L.-L Liu,F.-H Li,Y Zhang,X.-F Zhang,J Yang

doi:10.1590/1414-431x20175991

Abstract

Asthma is a chronic allergic disease characterized by airway inflammation, airway hyper-responsiveness (AHR), and mucus hypersecretion. T-lymphocytes are involved in the pathogenesis of asthma, mediating airway inflammatory reactions by secreting cytokines. The phosphoinositide 3-kinase (PI3K) and Notch signaling pathways are associated with T cell signaling, proliferation, and differentiation, and are important in the progression of asthma. Thus, compounds that can modulate T cell proliferation and function may be of clinical value. Here, we assessed the effects of tangeretin, a plant-derived flavonoid, in experimental asthma. BALB/c mice at postnatal day (P) 12 were challenged with ovalbumin (OVA). Separate groups of mice (n=18/group) were administered tangeretin at 25 or 50 mg/kg body weight by oral gavage. Dexamethasone was used as a positive control. Tangeretin treatment reduced inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) and also restored the normal histology of lung tissues. OVA-specific IgE levels in serum and BALF were reduced. AHR, as determined by airway resistance and lung compliance, was normalized. Flow cytometry analyses revealed a reduced Th17 cell population. Tangeretin reduced the levels of Th2 and Th17 cytokines and raised IFN-γ levels. PI3K signaling was inhibited. The expressions of the Notch 1 receptor and its ligands Jagged 1 and 2 were downregulated by tangeretin. Our findings support the possible use of tangeretin for treating allergic asthma.

Highlights

Asthma, an airway inflammatory disease, is common, chronic, and increasing in prevalence
The important role of T lymphocytes in the pathogenesis of asthma has been documented, and it involves the release of cytokines [28]
The CD4+ T cell cytokines are associated with cellular infiltration into the airways, mucus hypersecretion, eosinophil accumulation, airway hyper-responsiveness (AHR), and remodeling of the airways and lungs [28,29]

Summary

Introduction

An airway inflammatory disease, is common, chronic, and increasing in prevalence. It is associated with an extensive array of symptoms that include mucus hypersecretion, airway hyper-responsiveness (AHR), and airway remodeling [1]. T lymphocytes play major roles in airway inflammation and remodeling through cytokines [2]. Th2 cytokines (IL-4, IL-5, IL-13) induce allergen-specific immunoglobulin (Ig) E production and inflammatory mediator release from mast cells [2]. IFN-g, secreted by Th1 cells, suppresses Th2 immune responses. Class switching is induced by IL-4 in IgG1 and IgE, whereas IFN-g is associated with IgG2 a class switching [3]. Th1/Th2 cytokine stability is an important measure in the assessment of asthma [3]

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Conclusion