Tumor necrosis factor (TNF- ) receptor-II is required for TNF- –induced leukocyte-endothelial interaction in vivo

Tumor necrosis factor(TNF) binds to 2 distinct cell-surface receptors: TNFreceptor-I (TNFR-I: p55) and TNFreceptor-II (TNFR-II: p75). TNFinduces 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 wildtype (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 TNFactivation, 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 identificationofnovelp75-targeted therapeutic approaches for inflammatory diseases. (Blood. 2007;109:1938-1944)