E-selectin gene expression is induced synergistically with the coexistenceof activated classic protein kinase C and signals elicited by interleukin-1 beta but not tumor necrosis factor-alpha

We have examined the effect of protein kinase C (PKC) on the expression of the E-selectin and intercellular adhesion molecule-1 (ICAM-1) mRNAs in huma n umbilical vein endothelial cells. The lower classic PKC activity on pretr eatment with phorbol ester (phorbol 12-myristate 13-acetate (PMA)) for 24 h markedly decreased IL-1 beta-induced E-selectin mRNA expression in the pre sence of fetal calf serum and basic fibroblast growth factor, although the induction of ICAM-1 mRNA expression was only influenced a little by the PKC down-regulation. On the other hand, tumor necrosis factor-alpha (TNF alpha )-induced gene expression of these adhesion molecules was unaffected by suc h PKC modulation. The intracellular signals generated by interleukin (IL)-1 beta and TNF alpha themselves are not mediated through classic PKC activat ion, because the response to neither stimulant was inhibited by the PKC dow n-regulation in the absence of fetal calf serum and basic fibroblast growth factor. Simultaneous treatment with IL-1 beta and PMA synergistically indu ced E-selectin gene expression but not when TNFa was substituted for IL-1 b eta. ICAM-1 mRNA expression was only additively induced on the cotreatment. The synergistic effect on E-selectin mRNA induction was independent of de novo protein synthesis and mediated by elevated transcriptional activity. P romoter analysis of E-selectin indicated that the NF-ELAM1/activating trans cription factor element is critical for the synergistic effect of the cotre atment with IL-1 beta and PMA.