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) LTC(4)/LTD(4) and LTB(4). CysLT receptors are expressed in endothelial cells (EC) and EC cysLT(2)-R activation induces diverse pro-inflammatory genes in vitro. We now report that LTD(4) 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-PGF(1alpha), was increased several fold in LTD(4)-stimulated ECs, and was inhibited by the COX-2-specific inhibitor, NS-398. COX-2 up-regulation was Ca(2+)-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 cysLT(2)-R may limit its otherwise pro-inflammatory actions through a protective Ca(2+)/calcineurin/NFAT-dependent COX-2 feedback loop.
Lötzer
Katharina
K
Institute for Vascular Medicine, Friedrich-Schiller-University, Bachstrasse 18, 07743 Jena, Germany.
Jahn
Steffen
S
Kramer
Cornelia
C
Hildner
Markus
M
Nüsing
Rolf
R
Funk
Colin D
CD
Habenicht
Andreas J R
AJ
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D020013:Calcium Signaling; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D017998:Leukotriene D4 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020239:Receptor Cross-Talk; D018077:Receptors, Leukotriene / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation
D008565:Membrane Proteins; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; D016572:Cyclosporine; C412375:cysteinyl leukotriene receptor 2; D011464:Epoprostenol; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2