PLATELET-ACTIVATING-FACTOR STIMULATES INTERLEUKIN-6 PRODUCTION BY HUMAN ENDOTHELIAL-CELLS AND SYNERGIZES WITH TUMOR-NECROSIS-FACTOR FOR ENHANCED PRODUCTION OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR

The interaction between human endothelial cells (EC) and leukocytes du ring inflammation is in part mediated through the release of soluble f actors. Since platelet-activating factor (PAF) is a potent mediator of inflammatory responses, we investigated the potential of PAF to modul ate IL-6 and GM-CSF production by EC. Exposure of these cells to PAF r esulted in a concentration-dependent increase in IL-6 production, with a maximum at 10(-10) M PAE Sequential incubation of EC with PAF and T NF alpha resulted in a synergistic increase of IL-6 production. This e ffect was specific for PAF since it was prevented by preincubation wit h the PAF receptor antagonist, WEB 2086. Northern blot analysis reveal ed enhanced IL-6 mRNA expression in PAF-treated EC. However, the syner gy observed in protein synthesis between PAF and TNF alpha was not ref lected in IL-6 mRNA accumulation, suggesting a post-translational modu lation. Pretreatment of EC with the protein synthesis inhibitor cycloh eximide before their exposure to PAF resulted, after washout of the cy cloheximide, in a markedly augmented production of IL-6, suggesting a synergy between augmented IL-6 mRNA accumulation by PAF and IL-6 mRNA superinduction by cycloheximide. GM-CSF production by EC was also stim ulated by the combined effects of PAF and TNF alpha, but PAF alone did not affect GM-CSF production, Taken together, our data suggest that P AF can stimulate EC to synthesize cytokines, including IL-6 and GM-CSF , which may contribute to local and, possibly, systemic responses duri ng inflammation.