Tumor necrosis factor alpha (TNF-alpha) receptor-II is required for TNF-alpha-induced leukocyte-endothelial interaction in vivo.
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.
Chandrasekharan
Unni M
UM
Department of Cell Biology, Lerner Research Institute and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic Foundation, OH 44195, USA.
Siemionow
Maria
M
Unsal
Murat
M
Yang
Lin
L
Poptic
Earl
E
Bohn
Justin
J
Ozer
Kagan
K
Zhou
Zhongmin
Z
Howe
Philip H
PH
Penn
Marc
M
DiCorleto
Paul E
PE
D000818:Animals; D001772:Blood Cell Count; D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D019040:E-Selectin; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1