THE UP-REGULATION OF IL-6 AND IL-8 IN HUMAN ENDOTHELIAL-CELLS BY ACTIVATED PROTEIN-C

The protein C/protein S anticoagulant pathway has been proposed to be a common link between coagulation and inflammation. Studies have sugge sted that a component of the anticoagulant pathway, activated protein C (APC), may playa role in the inflammatory response by modulating the effects of cytokines such as TNF and by blocking neutrophil activatio n. Cytokines are known to be intimately involved in the inflammatory r esponse and to function in part to restore hemostatic balance. To begi n to delineate what role APC may have in the inflammatory response, we have investigated the effect of APC on the production of the proinfla mmatory cytokines IL-6 and IL-8 in primary HUVEC, human microvascular endothelial cells, and human coronary artery endothelial cells, Our re sults have demonstrated that physiologic concentrations of APC signifi cantly up-regulated the production of both IL-6 and IL-8, This increas e, which was seen at both the RNA and protein level, was not due to ei ther thrombin or LPS contamination of the APC preparation. Additional studies also showed that the APC-mediated up-regulation of IL-6 and IL -8 was IL-1 independent. Although neither purified protein C nor prote in S alone had an effect on cytokine production, protein S, the cofact or for APC, significantly enhanced the ability of APC to up-regulate I L-6/IL-8 production. These results provide further evidence for a role for APC in the inflammatory response.