Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia.
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.
Ahamed
Jasimuddin
J
The Rockefeller University, New York, NY, USA.
Niessen
Frank
F
Kurokawa
Toru
T
Lee
Young Kyung
YK
Bhattacharjee
Gourab
G
Morrissey
James H
JH
Ruf
Wolfram
W
D000818:Animals; D001777:Blood Coagulation; D003593:Cytoplasm / Q000737:chemistry; D019446:Endotoxemia / Q000097:blood* / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D013925:Thromboplastin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013925:Thromboplastin