Abstract
In human umbilical vein endothelial cells, treatment with tumor necrosis factor (TNF) -α stimulated the production of cellassociated interleukin (IL) -1α. Combined treatment of human umbilical vein endothelial cells with TNF-α and the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) suppressed the TNF-α-induced IL-1α production. However, concentrations of 6-keto-prostaglandin F1α in the conditioned medium were increased to a greater extent by combined treatment with TNF-α and TPA than by single treatment with TNF-α or TPA. Pretreatment with TPA for 15 min was enough to suppress the TNF-α-induced IL-1α production. Pretreatment for 15 min with other PKC activators such as aplysiatoxin (AT) or teleocidin (TC), also inhibited the TNF-α-induced IL-1α production. Stimulation of cell-associated IL-1α production by IL-1β or lipopolysaccharide (LPS) was also inhibited by treatment with the PKC activator TPA, AT or TC. However, treatment with the protein kinase inhibitor H-7 did not block the inhibitory effect of TPA, AT or TC on the cellassociated IL-1α production stimulated by TNF-α, IL-1β or LPS, although the PKC activator induced stimulation of 6-keto-prostaglandin F1α production was counteracted by H-7 treatment. These findings indicate that the production of cell-associated IL-1α stimulat-ed by TNF-α, IL-1β or LPS is inhibited by these PKC activators, but the inhibition by such PKC activators of IL-1α production is not due to PKC-dependent mechanism.
To further confirm this notion, effects of these drugs on IL-1 production by other cells were examined. In human pulmonary artery endothelial cells, these PKC activators inhibited cell-associated IL-1α production stimulated by TNF-α, IL-1β or LPS, and this inhibitory effect was not counteracted by the PKC inhibitor H-7 or staurosporine. In contrast, in human epithelial cell line NCI-H292, these PKC activators further enhanced LPS-induced IL-1α production. In addition, IL-1β production by human dermal fibroblasts and human promyelocytic leukemia cell line HL-60 stimulated by LPS or TNF-α was enhanced by these PKC activators. These results suggest that the suppression of IL-1α production by these PKC activators is a specific event to vascular endothelial cells.
