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Blood. 2007 Mar 1;109(5):1938-44. Epub 2006 Oct 26.

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

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  • 1Department of Cell Biology, Lerner Research Institute and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic Foundation, OH 44195, USA.


Tumor necrosis factor-alpha (TNF-alpha) binds to 2 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 (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-alpha-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-alpha-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-alpha-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-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.

[PubMed - indexed for MEDLINE]
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