| First Author | Ahamed J | Year | 2007 |
| Journal | Blood | Volume | 109 |
| Issue | 12 | Pages | 5251-9 |
| PubMed ID | 17332247 | Mgi Jnum | J:145422 |
| Mgi Id | MGI:3834541 | Doi | 10.1182/blood-2006-10-051334 |
| Citation | Ahamed J, et al. (2007) Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia. Blood 109(12):5251-9 |
| abstractText | Tissue factor (TF) is the primary initiator of coagulation, and the TF pathway mediates signaling through protease-activated receptors (PARs). In sepsis, TF is up-regulated as part of the proinflammatory response in lipopolysaccharide (LPS)-stimulated monocytes leading to systemic coagulation activation. Here we demonstrate that TF cytoplasmic domain-deleted (TF(Delta CT)) mice show enhanced and prolonged systemic coagulation activation relative to wild-type upon LPS challenge. However, TF(Delta CT) mice resolve inflammation earlier and are protected from lethality independent of changes in coagulation. Macrophages from LPS-challenged TF(Delta CT) 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 TF(Delta CT) mice. Increased TF expression of TF(Delta CT) macrophages does not require PAR2 and is specific for toll-like receptor, but not interferon gamma 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 TF(Delta CT) 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. |
