Leptin Is Oversecreted by Respiratory Syncytial Virus-Infected Bronchial Epithelial Cells and Regulates Th2 and Th17 Cell Differentiation

Abstract

Background: Infection of human bronchial epithelial cells (hBECs) with respiratory syncytial virus (RSV) has been shown to induce a Th lymphocyte subset drift, e.g. enhanced differentiation of Th2 and Th17 subsets, which is a classic characteristic of asthma. However, the molecules responsible for the drift in Th subsets remain unknown. This study aims to determine the expression of leptin in RSV-infected hBECs, and its role in Th2 and Th17 cell differentiation and extracellular regulated kinase (ERK) 1/2 phosphorylation. Methods: Cultured hBECs were infected with RSV. mRNA expression of the LEP gene in cells was measured by real-time PCR while LEP protein secretion in culture medium was measured by ELISA. Th differentiation was investigated in cultured human peripheral blood mononuclear cells following stimulation with recombinant human leptin. Th2 and Th17 subsets were examined by flow cytometry. Phosphorylation of the ERK1/2 protein in lymphocytes was detected by Western blot and immunofluorescence. Results: LEP mRNA expression was significantly upregulated in RSV-infected hBECs while the leptin protein level in the supernatants of RSV-infected hBECs was significantly increased. Stimulation of lymphocytes with leptin increased the differentiation of the Th17 subset and ERK1/2 phosphorylation, but suppressed Th2 subset differentiation. Conclusion: Leptin was oversecreted by RSV-infected hBECs, which promoted Th17 subset differentiation but suppressed Th2 subset differentiation possibly via regulating ERK1/2 phosphorylation.

Leptin gene polymorphism affects leptin level in childhood asthma

“…The interesting observation from our study is that leptin level is significantly increased during asthma exacerbation suggesting its role in active inflammatory processes. This is in line with the previous studies that showed increased secretion of leptin by epithelial cells infected with respiratory syncytial viral virus in vitro [ 9 ] and also in clinical setting that upon allergen challenge, leptin level was significantly higher during pollen season in seasonal allergic rhinitis patients than outside pollen season [ 18 ]. It was also shown that asthmatic children presented with increased serum leptin levels on admission, and the level decreased after 4 weeks of anti-inflammatory treatment [ 12 ].…”

“…Recent in vitro studies also showed that viral infection, the main cause of asthma exacerbations, led to increased secretion of leptin by bronchial epithelial cells resulting in activation of Th17 cells differentiation, and inhibition of Th2 cells differentiation [ 9 ]. These findings were confirmed by another in vitro study showing that leptin enhanced airway inflammation via increased intercellular adhesion molecule-1 expression and migration as well as cytokine synthesis in the human airway epithelium [ 10 ].…”

Regulatory T cells and T helper 17 cells in viral infection

“…A couple of mechanisms were proposed for increased Th17 cells and IL‐17 level. Firstly, leptin, which is excessively secreted by RSV‐infected hBECs, facilitates Th17 cell differentiation . Secondly, in the mice acutely infected with RSV, increased release of tachykinin and substance P led to C3a secretion by CD11b + bone marrow cells and subsequent increased secretion of IL‐17A .…”

Leptin Functions in Infectious Diseases

“…Furthermore, mice lacking functional leptin receptor in tissue- specific lung epithelial and macrophage cells have improved viral clearance and reduced lung injury following influenza-A infection suggesting that leptin signaling is also associated with non-myeloid cells such as natural killer cells and T cells ( 125 ). Leptin significantly upregulated the Th17 subset but suppressed Th2 subset differentiation possibly via regulating ERK1/2 phosphorylation in human bronchial epithelial cells (hBECs) infected with the respiratory syncytial virus (RSV) ( 126 ). Human immunodeficiency virus (HIV)-infected patients have an exaggerated expression of leptin receptor on their blood mononuclear cells while low leptin levels in their serum leads to an immune deficiency in these patients ( 127 , 128 ).…”