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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1938-1944.
Prepublished online as a Blood First Edition Paper on October 26, 2006; DOI 10.1182/blood-2006-05-020875.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Tumor necrosis factor  (TNF-) receptor-II is required for TNF-–induced leukocyte-endothelial interaction in vivo
Unni M. Chandrasekharan1,
Maria Siemionow2,
Murat Unsal2,
Lin Yang1,
Earl Poptic1,
Justin Bohn1,
Kagan Ozer2,
Zhongmin Zhou3,
Philip H. Howe1,
Marc Penn1,3, and
Paul E. DiCorleto1
1 Department of Cell Biology,
2 Department of Plastic and Reconstructive Surgery, and
3 Department of Cardiovascular Medicine, Lerner Research Institute and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic Foundation, OH
Tumor necrosis factor- (TNF-) binds to 2 distinct cell-surface receptors: TNF- receptor-I (TNFR-I: p55) and TNF- receptor-II (TNFR-II: p75). TNF- induces leukocyte adhesion molecules on endothelial cells (ECs), which mediate 3 defined steps of the inflammatory response; namely, leukocyte rolling, firm adhesion, and transmigration. In this study, we have investigated the role of p75 in TNF-–induced leukocyte adhesion molecules using cultured ECs derived from wild-type (WT), p75-null (p75–/–), or p55-null (p55–/–) mice. We observed that p75 was essential for TNF-–induced E-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) expression. We also investigated the putative role of p75 in inflammation in vivo using an intravital microscopic approach with a mouse cremaster muscle model. TNF-–stimulated leukocyte rolling, firm adhesion to ECs, and transmigration were dramatically reduced in p75–/– mice. Transplanted WT cremaster in p75–/– mice showed a robust leukocyte rolling and firm adhesion upon TNF- activation, suggesting that the impairment in EC-leukocyte interaction in p75–/– mice is due to EC dysfunction. These results demonstrate, for the first time, that endothelial p75 is essential for TNF-–induced leukocyte–endothelial-cell interaction. Our findings may contribute to the identification of novel p75-targeted therapeutic approaches for inflammatory diseases.
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