ENDOTHELIAL-CELL PROTEIN-S SYNTHESIS IS UP-REGULATED BY THE COMPLEX OF IL-6 AND SOLUBLE IL-6 RECEPTOR

We have recently demonstrated that the proinflammatory cytokine, inter leukin-6 (IL-6), could upregulate the production of protein S in the h uman hepatoma cell line, HepG-2, but not in endothelial cells. In this study, we have demonstrated that the combination of exogenous IL-6 an d soluble IL-6 receptor (sIL-6R) could significantly upregulate protei n S production in both primary human umbilical vein endothelial cells (HUVEC) and in the immortalized human microvascular endothelial cell l ine, HMEC-1. The IL-6/sIL-6R complex was also able to rapidly induce t yrosine phosphorylation of the IL-6 transducer, gp 130. Neutralizing a ntibodies directed against either IL-6 or gp130 blocked protein S upre gulation by the IL-6/sIL-6R complex. It was also observed that exogeno us sIL-6R could also upregulate protein S by forming a complex with IL -6 constitutively produced by the endothelial cell. Two other cytokine s which also utilize the gp130 receptor, oncostatin M (OSM) and leukem ia inhibitory factor (LIF), were also able to upregulate endothelial c ell protein S. This study demonstrates a mechanism that allows endothe lial cells to respond to IL-6 and also illustrates the potential impor tance of circulating soluble receptors in the regulation of the antico agulation pathway.