The cytoplasmic domain of tissue factor contributes to leukocyte recruitment and death in endotoxemia.
Tissue factor (TF) is an integral membrane protein that binds factor VIIa and initiates coagulation. The extracellular domain of TF is responsible for its hemostatic function and by implication in the dysregulation of coagulation, which contributes to death in endotoxemia. The role of the cytoplasmic domain of tissue factor in endotoxemia was studied in mice, which lack the cytoplasmic domain of TF (TF(deltaCT/deltaCT)). These mice develop normally and have normal coagulant function. Following i.p injection with 0.5 mg of lipopolysaccharide (LPS), TF(deltaCT/deltaCT) mice showed significantly greater survival at 24 hours compared to the wt mice (TF(+/+)). The serum levels of TNF-alpha and IL-1beta were significantly lower at 1 hour after LPS injection and IL-6 levels were significantly lower at 24 hours in TF(deltaCT/deltaCT) mice compared to TF(+/+)mice. Neutrophil recruitment into the lung was also significantly reduced in TF(deltaCT/deltaCT) mice. Nuclear extracts from tissues of endotoxemic TF(deltaCT/deltaCT) mice also showed reduced NFkappaB activation. LPS induced leukocyte rolling, adhesion, and transmigration in post-capillary venules assessed by intravital microscopy was also significantly reduced in TF(deltaCT/deltaCT) mice. These results indicate that deletion of the cytoplasmic domain of TF impairs the recruitment and activation of leukocytes and increases survival following endotoxin challenge.
Sharma
Laveena
L
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Level 5 Monash Medical Center, 246 Clayton Road, Clayton, Victoria 3168, Australia.
Melis
Els
E
Hickey
Michael J
MJ
Clyne
Colin D
CD
Erlich
Jonathan
J
Khachigian
Levon M
LM
Davenport
Piers
P
Morand
Eric
E
Carmeliet
Peter
P
Tipping
Peter G
PG
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D016923:Cell Death / Q000235:genetics*; D003593:Cytoplasm / Q000737:chemistry; D019446:Endotoxemia / Q000139:chemically induced / Q000503:physiopathology*; D004926:Escherichia coli; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007274:Injections, Intraperitoneal; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000097:blood / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion; D013925:Thromboplastin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D013925:Thromboplastin