Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor κB (NF-κB) and tumour necrosis factor α (TNF-α) production in the THP-1 monocytic cell line

Activated protein C (APC) protects against sepsis in animal models and inhibits the lipopolysacharide (LPS)-induced elaboration of proinflammatory cytokines from monocytes. The molecular mechanism responsible for this property is unknown. We assessed the effect of APC on LPS-induced tumour necrosis factor alpha (TNF-alpha) production and on the activation of the central proinflammatory transcription factor nuclear factor-kappa B (NF-kappa B) in a THP-1 cell line. Cells were preincubated with varying concentrations of APC (200 mu g/ml. 100 mu g/ml and 20 mu g/ml) before addition of LPS (100 ng/ml and 10 mu g/ml). APC inhibited LPS-induced production of TNF-alpha both in the presence and absence of fetal calf serum (FCS), although the effect was less marked with 10% FCS. APC also inhibited LPS-induced activation of NF-kappa B, with APC (200 mu g/ mi) abolishing the effect of LPS (100 ng/ml). The ability of APC to inhibit LPS-induced translocation of NF-kappa B is likely to be a significant event given the critical role of the latter in the host inflammatory response.