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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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Submitted May 5, 2006
Accepted October 21, 2006

TNF-{alpha} receptor-II is required for TNF-{alpha}- induced leukocyte-endothelial interaction in vivo

Unni M Chandrasekharan, Maria Siemionow, Murat Unsal, Lin Yang, Earl Poptic, Justin Bohn, Kagan Ozer, Zhongmin Zhou, Philip H Howe, Marc Penn, and Paul E DiCorleto*

Dept of Cell Biology, Lerner Research Institute, Cleveland, OH, United States
Dept of Plastic & Reconstructive Surgery, Cleveland Clinic, OH, United States
Dept of Cardiovascular Medicine, Cleveland Clinic, OH, United States

* Corresponding author; email: dicorlp{at}ccf.org.

Tumor necrosis factor-{alpha} (TNF-{alpha}) binds to two distinct cell surface receptors; TNF-{alpha} receptor-I (TNFR-I: p55) and TNF-{alpha} receptor-II (TNFR-II: p75). TNF-{alpha} induces leukocyte adhesion molecules on endothelial cells (EC) which mediate three 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-{alpha}-induced leukocyte adhesion molecules using cultured EC derived from WT, p75-null (p75-/-) or p55-null (p55-/-) mice. We observed that p75 was essential for TNF-{alpha}-induced E-selectin, VCAM-1 and 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-{alpha}-stimulated leukocyte rolling, firm adhesion to EC and transmigration were dramatically reduced in p75-/- mice. Transplanted wild type cremaster in p75-/- mice showed a robust leukocyte rolling and firm adhesion upon TNF-{alpha} 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-{alpha}-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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