Leptin enhances ICAM-1 expression, induces migration and cytokine synthesis, and prolongs survival of human airway epithelial cells

Abstract

There is rising interest in how obesity affects respiratory diseases, since epidemiological findings indicate a strong relationship between the two conditions. Leptin is a potent adipokine produced mainly by adipocytes. It regulates energy storage and expenditure and also induces inflammation. Previous studies have shown that leptin is able to activate inflammatory cells such as lymphocytes and granulocytes, but little is known about its effect on lung structural cells. The present study investigated the effects of leptin on human airway epithelial cells by using human primary airway epithelial cells and a human airway epithelial cell line, BEAS-2B. Flow cytometry showed enhanced ICAM-1 expression by both of those cells in response to leptin, and that effect was abrogated by dexamethasone or NF-κB inhibitor. Flow cytometry and quantitative PCR showed that airway epithelial cells expressed leptin receptor (Ob-R), whose expression level was downregulated by leptin itself. Multiplex cytokine analysis demonstrated enhanced production of CCL11, G-CSF, VEGF, and IL-6 by BEAS-2B cells stimulated with leptin. Furthermore, transfection of Ob-R small interference RNA decreased the effect of leptin on CCL11 production as assessed by quantitative PCR. Finally, leptin induced migration of primary airway epithelial cells toward leptin, suppressed BEAS-2B apoptosis induced with TNF-α and IFN-γ, and enhanced proliferation of primary airway epithelial cells. In summary, leptin was able to directly activate human airway epithelial cells by binding to Ob-R and by NF-κB activation, resulting in upregulation of ICAM-1 expression, induction of CCL11, VEGF, G-CSF, and IL-6 synthesis, induction of migration, inhibition of apoptosis, and enhancement of proliferation.

Obesity promotes prolonged ovalbumin-induced airway inflammation modulating T helper type 1 (Th1), Th2 and Th17 immune responses in BALB/c mice

“…This effect may have been mediated in part by the enhanced levels of leptin, which is known to promote the survival and activation of eosinophils . In addition, leptin could induce the recruitment of eosinophils by up‐regulation of CCL11 in epithelial cells . Collectively, our results are in agreement with clinical studies reporting obesity as an important determinant of the clinical asthma phenotype, which is characterized typically in humans by a scarce number of eosinophils in the sputum and reduced or normal levels of IgE .…”

Leptin gene polymorphism affects leptin level in childhood asthma

“…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 ].…”

Leptin Promotes cPLA2 Gene Expression through Activation of the MAPK/NF-κB/p300 Cascade

“…We report that leptin enhanced the mRNA and protein expression of cPLA 2 -α, which functions as an inflammation marker, in vitro in lung alveolar cells and in vivo in lung tissues. This conclusion is similar to previous findings that leptin induced gene expression of intracellular adhesion molecular-1, CCL11, VEGF, G-CSF, IL-6, and cell migration on the human airway epithelial cell line [ 41 ]. This is also similar to the conclusion that leptin triggers A549 cell proliferation through blockage of endoplasmic reticulum stress-related apoptosis [ 39 ].…”