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(American Journal of Pathology. 2004;165:331-340.)
© 2004 American Society for Investigative Pathology

The Cytoplasmic Domain of Tissue Factor Contributes to Leukocyte Recruitment and Death in Endotoxemia

Laveena Sharma*, Els Melis{dagger}, Michael J. Hickey*, Colin D. Clyne{ddagger}, Jonathan Erlich§, Levon M. Khachigian, Piers Davenport*, Eric Morand*, Peter Carmeliet{dagger} and Peter G. Tipping*

From the Centre for Inflammatory Diseases,* Department of Medicine, Monash University, Clayton Victoria, Australia; the Centre for Transgene Technology and Gene Therapy,{dagger} Campus Gasthuisberg, Leuven, Belgium; Prince Henry’s Institute of Medical Research,{ddagger} Clayton Victoria, Australia; the Department of Nephrology,§ Prince of Wales Hospital, University of New South Wales, Randwick, New South Wales, Australia; and the Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Randwick, New South Wales, Australia

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{delta}CT/{delta}CT). These mice develop normally and have normal coagulant function. Following i.p injection with 0.5 mg of lipopolysaccharide (LPS), TF{delta}CT/{delta}CT mice showed significantly greater survival at 24 hours compared to the wt mice (TF+/+). The serum levels of TNF-{alpha} and IL-1ß were significantly lower at 1 hour after LPS injection and IL-6 levels were significantly lower at 24 hours in TF{delta}CT/{delta}CT mice compared to TF+/+mice. Neutrophil recruitment into the lung was also significantly reduced in TF{delta}CT/{delta}CT mice. Nuclear extracts from tissues of endotoxemic TF{delta}CT/{delta}CT mice also showed reduced NF{kappa}B activation. LPS induced leukocyte rolling, adhesion, and transmigration in post-capillary venules assessed by intravital microscopy was also significantly reduced in TF{delta}CT/{delta}CT 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.




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