Leptin induces the expression of functional tissue factor in human neutrophils and peripheral blood mononuclear cells through JAK2-dependent mechanisms and TNF alpha involvement
AuthorRafail, S.; Ritis, K.; Schaefer, K.; Kourtzelis, I.; Speletas, M.; Doumas, M.; Giaglis, S.; Kambas, K.; Konstantinides, S.; Kartalis, G.
Introduction: Leptin is an adipocyte-derived cytokine primarily involved in the regulation of body weight and energy balance. In vivo studies suggest that leptin promotes platelet aggregation and thrombosis. Neutrophils are involved in the crosstalk between inflammation and thrombosis in clinical disorders. Leptin is also involved in the regulation of inflammation. Aim: We examined the in vitro effects of leptin on the expression of tissue factor (TF), the primary initiator of coagulation, in healthy neutrophils. Materials and methods/results: The effects on TF expression were assayed functionally using a modified prothrombin time (mPT), as well as at mRNA and protein levels. The same experiments were performed in parallel with PBMC. Leptin induced functional TF and increased TF mRNA and protein expression in both cell types, as determined by mPT, real-time RT-PCR, western blot, flow cytometry, immunocytochemistry. Inhibition studies revealed that the effect of leptin on TF expression is mediated, at least in part, by JAK2 and PI3K. Our findings, after neutralising TNF alpha in supernatants of leptin-treated cells, also suggest the involvement of TNF alpha in the leptin-induced TF expression in leukocytes. Conclusions: This study indicates a novel link between inflammation, obesity and thrombosis by showing that leptin is able to trigger the extrinsic coagulation cascade. This work suggests a possible mechanism of the thrombotic effects of hyperleptinemic-associated clinical disorders. (C) 2007 Elsevier Ltd. All rights reserved.