Leukotriene D4 enhances tumor necrosis factor-α-induced vascular endothelial growth factor production in human monocytes/macrophages

Background: Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic mitogens specific for vascular endothelial cells. It also induces vascular hyperpermeability and protein leakage into the extracellular space. Leukotriene D-4 (LTD4), one of the cysteinyl leukotrienes (CysLTs), is known to be one of the key molecules of allergic inflammation. The interaction between LTD4 and VEGF production in human monocytes/macrophages is not well characterized. Methods: We examined VEGF production by THP-1 cells, a human monocytic leukemia cell line, and human peripheral blood CD14 + monocytes/macrophages stimulated with LTD4 and/or tumor necrosis factor-alpha (TNF-alpha). We also determined the inhibitory effects of pranlukast, a CysLT(1) receptor antagonist, on VEGF production by LTD4 stimulation. Results: LTD4 significantly induced VEGF production and enhanced TNF-alpha-induced VEGF release in THP-1 cells and human peripheral blood CD14 + monocytes/macrophages. VEGF mRNA expression was also induced by stimulation of THP-1 cells with LTD4 and TNF-alpha. In addition, 10(-7)-10(-10) M pranlukast completely inhibited VEGF production enhanced by LTD4. The 50% inhibitory concentration (IC50) for VEGF production in THP-1 cells was 10(-10)-10(-11) M. Conclusions: LTD4 induced VEGF production and enhanced VEGF release induced by TNF-alpha via CysLT(1) receptors in human monocytes/macrophages. These effects were completely inhibited by pranlukast. (C) 2011 Elsevier Ltd. All rights reserved.