Tumor necrosis factor induces a selective shedding of its p75 receptor from human neutrophils.
The effect of tumor necrosis factor alpha (TNF) on the expression of its specific receptors (p55 TNF-R and p75 TNF-R) on the surface of human neutrophils (PMN) and mononuclear cells (MNC) was investigated and compared to the effect of various agonists. PMN and MNC express both p55 and p75 TNF-R on their membranes. Within minutes of incubation with chemotactic factors or calcium ionophore A23187, both types of TNF-R were down-regulated from the surface on both cell populations. At the same time, soluble forms of these TNF-R appeared in supernatants, in amounts proportional to the extent of down-regulation induced by each stimulus, suggesting that shedding is the major mechanism leading to loss of p55 and p75 TNF-R upon activation with these agonists. Likewise, TNF induced 60-80% and 73-90% decreases in PMN surface p55 TNF-R and p75 TNF-R, respectively. However, modulation of the two types of TNF-R by TNF proceeded through different mechanisms. TNF induced a selective shedding of the p75 TNF-R since, by both enzyme-linked immunosorbent assay and Western blot analysis, only the p75 TNF-R was detected in supernatants of cells stimulated with TNF. Down-modulation of surface p55 TNF-R most probably resulted from TNF-induced receptor internalization, since 125I-TNF bound to PMN p55 TNF-R was rapidly internalized with a t1/2 = 5 min and preincubation of PMN with TNF inhibited by 68 +/- 6% the release of p55 TNF-R triggered upon subsequent treatment with A23187. The apparently unique property of TNF to induce a differential modulation of the two types of TNF-R at the surface of PMN and MNC might play an important role in the control of peripheral blood cell responses to TNF.
Porteu
F
F
Institut National de la Santé et de la Recherche Médicale U90, Hôpital Necker, Paris, France.
Hieblot
C
C
D000328:Adult; D000001:Calcimycin / Q000494:pharmacology; D015936:Complement C5a / Q000494:pharmacology; D015536:Down-Regulation; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008970:Molecular Weight; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a