5-Lipoxygenase/cyclooxygenase-2 cross-talk through cysteinyl leukotriene receptor 2 in endothelial cells

The 5-lipoxygenase (5-LO) pathway generates lipid mediators, i.e. the cysteinyl leukotrienes (cysLTs) LTC4/LTD4 and LTB4. CysLT receptors are expressed in endothelial cells (EC) and EC cysLT2-R activation induces diverse pro-inflammatory genes in vitro. We now report that LTD4 promotes formation of an atherosclerosis-protective and anti-thrombotic eicosanoid by markedly up-regulating EC cyclooxygenase-2 (COX-2). CysLT-induced COX-2 transcripts were transiently up-regulated as determined by microarray and QRT-PCR analyses though COX-2 protein remained elevated for several hours. Prostacyclin formation, measured as its stable metabolite 6-keto-PGF1α, was increased several fold in LTD4-stimulated ECs, and was inhibited by the COX-2-specific inhibitor, NS-398. COX-2 up-regulation was Ca2+-dependent and was partially blocked by cyclosporin A indicating that the 5-LO/COX-2 cross-talk involved signaling through a nuclear factor of activated T cells (NFAT) dependent pathway. Since prostacyclin is a major blood vessel-protective and anti-thrombotic eicosanoid, the EC cysLT2-R may limit its otherwise pro-inflammatory actions through a protective Ca2+/calcineurin/NFAT-dependent COX-2 feedback loop.