IL-6 UP-REGULATES PROTEIN-S EXPRESSION IN THE HEPG-2 HEPATOMA-CELLS

Several pro-inflammatory cytokines have been shown to be important in the modulation of the procoagulant response. However, what role these cytokines may have in the regulation of coagulation inhibitors is poor ly understood. While the hepatocyte is a primary site of synthesis for the anticoagulant proteins C and S, it is also major target cell for the proinflammatory cytokine, IL-6. We have found that stimulation of HepG-2 hepatoma cells with IL-6 (5 ng/ml) significantly increased the production of the anticoagulant cofactor, protein S, in both a time an d dose dependent fashion. This increase was seen at both the RNA and p rotein level. A mouse monoclonal neutralizing antibody to human IL-6 s uppressed the IL-6 effect in a concentration dependent fashion. IL-6 a lso increased the release of the C4b-binding protein but had no effect on protein C production. When combined with either dexamethasone or s oluble IL-6 receptor, the IL-6 response was significantly enhanced. On costatin M, a functionally related cytokine, had a similar effect whil e other related cytokines, IL-11 and leukemia inhibitory factor, only had a marginal effect. IL-1, TGF-beta, and TNF-alpha had no significan t effect on protein S production. These results indicate that IL-6 may play an important regulatory role in the anticoagulant pathway.