Agonist-specific cross talk between ERKs and p38mapk regulates PGI2 synthesis in endothelium

Abstract

We have examined the mechanisms regulating prostacyclin (PGI2) synthesis after acute exposure of human umbilical vein endothelial cells (HUVEC) to interleukin-1α (IL-1α). IL-1α evoked an early (30 min) release of PGI2 and [3H]arachidonate that was blocked by the cytosolic phospholipase A2α (cPLA2α) inhibitor arachidonyl trifluoromethyl ketone. IL-1α-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2; p42/p44mapk) coincided temporally with phosphorylation of cPLA2α and with the onset of PGI2synthesis. The mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors, PD-98059 and U-0126, blocked IL-1α-induced ERK activation and partially attenuated cPLA2α phosphorylation and PGI2 release, suggesting that ERK-dependent and -independent pathways regulate cPLA2α phosphorylation. SB-203580 treatment enhanced IL-1α-induced MEK, p42/44mapk, and cPLA2α phosphorylation but reduced thrombin-stimulated MEK and p42/44mapk activation. IL-1α, but not thrombin, activated Raf-1 as assessed by immune-complex kinase assay, as did SB-203580 alone. These results show that IL-1α causes an acute upregulation of PGI2generation in HUVEC, establish a role for the MEK/ERK/cPLA2α pathway in this early release, and provide evidence for an agonist-specific cross talk between p38mapkand p42/44mapk that may reflect receptor-specific differences in the signaling elements proximal to MAPK activation.