The isoprostane 8-iso-PGE2 stimulates endothelial cells to bind monocytes via cyclic AMP- and p38 MAP kinase-dependent signaling pathways

Increased levels of isoprostanes have been detected in human atherosclerotic lesions. To examine a possible role for 8-iso-prostaglandin E-2 (8-iso-PGE(2)) in atherogenesis, we tested the effect of 8-iso-PGE(2) on adhesion of leukocytes to human umbilical vein endothelial cells (EC). We demonstrate that 8-iso-PGE(2) stimulates EC to bind monocytes, but not neutrophils. This effect was inhibited by the thromboxane A 2 receptor antagonist SQ29548. Moreover, 8-iso-PGE(2) increased levels of cyclic AMP in EC, and monocyte adhesion induced by 8-iso-PGE(2) was blocked by a protein kinase A inhibitor, H89. In addition, 8-iso-PGE(2) induced phosphorylation of p38 and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein (MAP) kinase and stimulated expression of EGR-1. A specific inhibitor of p38 MAP kinase (SB203580) abrogated monocyte binding, whereas an inhibitor of the ERK pathway (PD98059) did not block monocyte adhesion induced by 8-iso-PGE(2). Activation of nuclear factor-kappaB (NF-kappaB) and expression of NFkappaB-dependent genes intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and F-selectin were not induced by 8-iso-PGE(2). Taken together, these results demonstrate that 8-iso-PGE(2) stimulates EC to specifically bind monocytes, but not neutrophils. This effect is mediated by cyclic AMP/protein kinase A- and p38 MAP kinase-dependent pathways and is independent of the classical inflammatory NFkappaB pathway. Thus, formation of 8-iso-PGE(2) may play an important role in chronic inflammatory diseases such as atherosclerosis by increasing adhesion and extravasation of monocytes.