Leukotriene D4 Stimulates the Migration but Not Proliferation of Endothelial Cells Mediated by the Cysteinyl Leukotriene CysLT1 Receptor via the Extracellular Signal-Regulated Kinase Pathway

Abstract

Abstract. The actions of cysteinyl leukotrienes (CysLTs) are mediated by activating CysLT receptors, CysLT 1 , and CysLT 2 . The CysLT 1 receptor mediates vascular responses to CysLTs; however, its effect on the proliferation and migration of endothelial cells is not clarified. To determine this effect, we observed proliferation and migration in EA.hy926 cells, a human endothelial cell line, and the involvement of activation of mitogen-activated protein kinases (MAPKs). We found that LTD 4 did not affect the proliferation, but significantly stimulated the migration of endothelial cells. LTD 4 also induced the phosphorylation of extracellular signalregulated kinase (ERK) 1 / 2, but not those of p38 or JNK. The LTD 4 -induced migration and ERK1/ 2 phosphorylation were blocked by the CysLT 1 -receptor antagonist montelukast and the dual antagonist Bay u9773, but not by the CysLT 2 -receptor antagonist Bay cysLT2; the migration was also inhibited by the ERK1/ 2 inhibitor U0126. Our findings indicate that LTD 4 stimulates the CysLT 1 receptor-mediated migration of endothelial cells; this may be regulated by the ERK1/ 2 pathway.

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…IL-8 induction has been studied in more detail, demonstrating that in HEK-293 cells stably transfected with CysLT 2 R LTC 4 transcriptionally activates its production through induction of NF-B and AP-1 transcription factors (Thompson et al, 2008a). However, at variance with the results in HUVECs, a recent article suggested that in EA.hy926 cells, a human EC line, LTD 4 induced the phosphorylation of ERK1/2, but not that of p38 or JNK and that these effects were blocked by the CysLT 1 R antagonist montelukast or by the dual antagonist BAY U9773, but not by a novel CysLT 2 R antagonist referred to as Bay cysLT 2 (Yuan et al, 2009). …”

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

“…39 It has been shown that LPS and CysLT induce the activation of ERK1/2 and p38. 41,42 Taking this into account, we decided to analyse the activation of ERK1/2 and p38 MAPK. Western blots of lysates from DCs cultured without or with LPS (1 lg/ml) for 30 min at 37°w ere incubated in the presence or not of LTC 4 (10 -8…”

Leukotriene D4 induces cognitive impairment through enhancement of CysLT1R-mediated amyloid-β generation in mice

“…However, it is not clear whether CysLTs and their receptors mediate pathogenesis of AD. It has been reported that LTD4 causes braineblood barrier (BBB) disruption and brain edema via its receptors (Wang et al, 2006;Yuan et al, 2009). The CysLT 1 R mediates astrocyte proliferation (Ciccarelli et al, 2004;Huang et al, 2008), brain cryoinjury, brain tumors and acute neuronal injury after focal cerebral ischemia in mice (Dinq et al, 2007;Zhang et al, 2004Zhang et al, , 2006.…”