Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia

Tissue factor (TIF) is the primary initiator of coagulation, and the TF pathway mediates signaling through protease-activated receptors (PARs). In sepsis, TF is upregulated as part of the proinflammatory response in lipopolysaccharide (LPS)stimulated monocytes leading to systemic coagulation activation. Here we demonstrate that TF cytoplasmic domain-deleted (TFICT) mice show enhanced and prolonged systemic coagulation activation relative to wild-type upon ILPS challenge. However, TFACT mice resolve inflammation earlier and are protected from lethality independent of changes in coagulation. Macrophages from LPS-challenged TFACT mice or LPS-stimulated, in vitro-differentiated bone marrow-derived macrophages show increased TF mRNA and functional activity relative to wild-type, identifying up-regulation of macrophage TF expression as a possible cause for the increase in coagulation of TFACT mice. Increased TF expression of TFACT macrophages does not require PAR2 and is specific for toll-like receptor, but not interferon,y receptor, signaling. The presence of the TF cytoplasmic domain suppresses ERK1/2 phosphorylation that is reversed by p38 inhibition leading to enhanced TF expression specifically in wild-type but not TFACT mice. The present study demonstrates a new role of the TF cytoplasmic domain in an autoregulatory pathway that controls LPS-induced TF expression in macrophages and procoagulant responses in endotoxemia.