Chandrasekharan, Unni M.;
Siemionow, Maria;
Unsal, Murat;
Yang, Lin;
Poptic, Earl;
Bohn, Justin;
Ozer, Kagan;
Zhou, Zhongmin;
Howe, Philip H.;
Penn, Marc;
DiCorleto, Paul E.
Tumor necrosis factor α (TNF-α) receptor-II is required for TNF-α–induced leukocyte-endothelial interaction in vivo
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Media type:
E-Article
Title:
Tumor necrosis factor α (TNF-α) receptor-II is required for TNF-α–induced leukocyte-endothelial interaction in vivo
Contributor:
Chandrasekharan, Unni M.;
Siemionow, Maria;
Unsal, Murat;
Yang, Lin;
Poptic, Earl;
Bohn, Justin;
Ozer, Kagan;
Zhou, Zhongmin;
Howe, Philip H.;
Penn, Marc;
DiCorleto, Paul E.
Published:
American Society of Hematology, 2007
Published in:
Blood, 109 (2007) 5, Seite 1938-1944
Language:
English
DOI:
10.1182/blood-2006-05-020875
ISSN:
0006-4971;
1528-0020
Origination:
Footnote:
Description:
AbstractTumor necrosis factor-α (TNF-α) binds to 2 distinct cell-surface receptors: TNF-α receptor-I (TNFR-I: p55) and TNF-α receptor-II (TNFR-II: p75). TNF-α 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-α–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-α–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-α–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-α 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-α–induced leukocyte–endothelial-cell interaction. Our findings may contribute to the identification of novel p75-targeted therapeutic approaches for inflammatory diseases.