Factor Xa induces pro-inflammatory cytokine expression in RAW 264.7 macrophages via protease-activated receptor-2 activation.

Coagulation proteases have been suggested to trigger a diversity of inflammatory responses in addition to their critical role in the coagulation cascade. It has been well established that the inflammatory and coagulation pathways are invariably linked. However, the mechanisms through which coagulation protease factor Xa (FXa) causes inflammation remain unclear. Thus, we assessed the pro-inflammatory effects of FXa in RAW 264.7 macrophages. We show that FXa elicits signal transduction in RAW 264.7 macrophages. FXa-induced signal transduction was dependent on the activation of protease-activated receptor 2 (PAR-2), PAR-2 desensitization but not PAR-1 desensitization abolished FXa-induced ERK1/2 phosphorylation. The PAR-2-dependent cellular effects of FXa led to the expression of pro-inflammatory cytokines IL-6, IL-8, TNF-α and IFN-γ in RAW 264.7 macrophages. Furthermore, a specific inhibitor of the ERK1/2 pathway, U0126, decreased the FXa-induced pro-inflammatory cytokines expression significantly. Taken together, our data indicate that FXa induces PAR-2-dependent pro-inflammatory activity in RAW 264.7 macrophages through the ERK1/2 pathway.