Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages

The potential for tissue factor (TF) to enhance inflammation by factor VIIa -dependent induction of proinflammatory changes in macrophages was explored . Purified recombinant human factor VIIa enhanced reactive oxygen species p roduction by human monocyte-derived macrophages expressing TF in vitro. Thi s effect was dose- and time-dependent, ligand- and receptor-specific, and i ndependent of other coagulation proteins, This receptor/ligand binding indu ced phospholipase C-dependent intracellular calcium fluxes. Transfection st udies using a human monocyte-derived cell line (U937) demonstrated that an intact intracytoplasmic domain of TF is required for factor VIIa-induced in tracellular calcium fluxes. The capacity of TF to enhance proinflammatory f unctions of rabbit peritoneal-elicited macrophages (production of reactive oxygen species and expression of major histocompatibility complex class II and cell adhesion molecules) was demonstrated in vivo by treatment with an anti-TF antibody. These data demonstrate that, in addition to its role in a ctivation of coagulation, TF can directly augment macrophage activation. Th ese effects are initiated by binding factor VIIa and are independent of oth er coagulation proteins. These studies provide the first demonstration of a direct proinflammatory role for TF acting as a cell-signaling receptor. (C ) 1999 by The American Society of Hematology.