Agonist-specific cross talk between ERKs and p38mapkregulates PGI2synthesis in endothelium

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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 PGI2and [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 PGI2release, 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 p42/44mapkactivation. 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 p42/44mapkthat may reflect receptor-specific differences in the signaling elements proximal to MAPK activation.

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