Leptin augments alveolar macrophage leukotriene synthesis by increasing phospholipase activity and enhancing group IVC iPLA₂(cPLA₂γ) protein expression

Abstract

Leptin is a hormone secreted by adipocytes in correlation with total body fat mass. In addition to regulating energy homeostasis, leptin modulates immune functions such as macrophage phagocytosis and cytokine synthesis. Previously, we reported defective leukotriene synthesis in macrophages from leptin-deficient mice that could be restored with exogenous leptin. In the present study, we utilized macrophages from normal rodents to explore the mechanism by which leptin could enhance cellular leukotriene synthesis. Leptin pretreatment of either rat alveolar or murine peritoneal macrophages for 16 h dose dependently increased the synthesis of leukotriene B4 and cysteinyl leukotrienes in response to calcium ionophore or the particulate zymosan. Leptin also enhanced calcium ionophore-stimulated release of free arachidonic acid. Calcium-dependent and -independent arachidonoyl-selective phospholipase activities in macrophage lysates were likewise increased following leptin treatment. Immunoblot analysis of leptin-treated cells revealed that group IVC iPLA2 (cPLA2gamma) protein expression increased approximately 80%. These data demonstrate for the first time that phospholipase A2 activity and cPLA2gamma protein levels in alveolar macrophages represent targets for upregulation by leptin and provide previously unrecognized mechanisms by which this hormone can promote inflammatory responses.

Influence of body mass index on the response to asthma controller agents

“…The fact that therapeutic responses to montelukast appeared to increase with increasing BMI suggests that asthma in the overweight and the obese may be a more LT-driven form of asthma than in individuals of normal BMI. This could potentially be explained by the previous demonstration [41,42] that LT biosynthetic capacity and expression of enzymes in the LT biosynthetic pathway can be upregulated in vitro and in vivo by leptin, an adipocyte-derived hormone whose serum levels parallel total body fat mass [43,44] and that has been increasingly implicated as a mediator of inflammation [45] and immune responses [46], as well as atopic asthma [47]. It can be speculated that leptin may provide a link between increasing BMI and the relative importance of LTs as mediators driving asthma.…”

Leptin and Inflammation

“…On monocytes leptin also upregulates the expression of human leukocyte antigen (HLA)-DR [68] and stimulates the production of of IL-6 and TNF-α [68]. Leptin activates macrophages, enhances their phagocytic activity through phospholipase activation [69] and induces them to produce eicosanoids, nitric oxide, leukotriene B4, cholesterol acyltransferases-1, and cyclooxygenase 2, and other pro-inflammatory cytokines [68,[70][71].…”

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

“…Leptin is a 16-kDa protein synthesized by adipocytes that was initially recognized for its role in the regulation of food intake and energy balance, but which has more recently been recognized to also influence inflammatory and immune processes (73). Macrophage LT synthesis was recently found to be reduced in leptin-deficient mice, and this defect was associated with impaired innate immune responses following intrapulmonary challenge with K. pneumoniae (74); the addition of exogenous leptin in vitro restored cellular LT synthetic capacity and the relevant enzymatic mechanisms have recently been identified (75).…”