Signal transduction pathways involved in lipopolysaccharide-induced production of PGE2 by human microvascular endothelial cells

Abstract

Lipopolysaccharide induces the expression of prostaglandin H synthase-2 with subsequent production of PGE₂ in human microvascular endothelial cells. In order to investigate the signaling pathways that are involved in the LPS-induced production of PGE₂, the roles of several second messenger systems in this process were evaluated. Treatment of human microvascular endothelial cells with the tyrosine kinase inhibitors herbimycin A and genistein significantly inhibited LPS-mediated PGE₂ production. Western blotting demonstrated that LPS induced the phosphorylation of p42, p44 and p38 MAP kinases. Both PD98059, an inhibitor of p42 and p44 MAP kinase activation, and SB203580, an inhibitor of p38 MAP kinase, blocked LPS-induced PGE₂ production. Inhibition of PKC activity by staurosporine and GF109203X resulted in a potentiation of the LPS response. Treatment of the cells with SN50, an NF-κB inhibitor, resulted in inhibition of the LPS-mediated PGE₂ production. These results suggest that LPS induces PGE₂ production in human microvascular endothelial cells through sequential activation of tyrosine kinases, ERK and p38 MAP kinases and NF-κB. In addition, PKC activity exerts a feedback control of PGE₂ production in LPS-stimulated microvessel-derived endothelial cells.

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