Tumor necrosis factor activates human endothelial cells through the p55 tumor necrosis factor receptor but the p75 receptor contributes to activation at low tumor necrosis factor concentration.
Tumor necrosis factor-alpha (TNF-alpha) interacts with two distinct membrane receptor proteins, p55 and p75, which are variably expressed on different cell types. We have examined the function of p55 and p75 on human endothelial cells (EC). Both receptor types are detected on cultured EC by FACS analysis. A mutagenized recombinant human TNF (R32W-TNF), which binds selectively to p55, is equipotent with human recombinant wild-type TNF (wt-TNF) in upregulating several different leukocyte adhesion molecules as well as class I major histocompatibility complex molecules. R32W-TNF also fully desensitizes EC to wt-TNF, as assessed by inhibition of re-induction of endothelial leukocyte adhesion molecule-1 (ELAM-1). At low wt-TNF concentrations, induction of ELAM-1 is partly inhibited by blocking monoclonal antibodies to either p55 or p75 and to a greater extent by a combination of both monoclonal antibodies. In contrast, ELAM-1 induction by R32W-TNF is only inhibited by anti-p55. We conclude that both TNF receptors (p55 and p75) can contribute to TNF-induced activation of EC, but that signaling through p55 is sufficient.
Slowik
M R
MR
Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-0812.
De Luca
L G
LG
Fiers
W
W
Pober
J S
JS
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000166:cytology* / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007457:Iodine Radioisotopes; D008970:Molecular Weight; D011233:Precipitin Tests; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis* / Q000737:chemistry / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D007457:Iodine Radioisotopes; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha