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 i ts specific receptors (p55 TNF-R and p75 TNF-R) on the surface of huma n neutrophils (PMN) and mononuclear cells (MNC) was investigated and c ompared to the effect of various agonists. PMN and-MNC express both p5 5 and p75 TNF-R on their membranes. Within minutes of incubation with chemotactic factors or calcium ionophore A23187, both types of TNF-R w ere down-regulated from the surface on both cell populations. At the s ame time, soluble forms of these TNF-R appeared in supernatants, in am ounts proportional to the extent of down-regulation induced by each st imulus, suggesting that shedding is the major mechanism leading to los s 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 p 75 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 su pernatants of cells stimulated with TNF. Down-modulation of surface p5 5 TNF-R most probably resulted from TNF-induced receptor internalizati on, since I-125-TNF bound to PMN p55 TNF-R was rapidly internalized wi th 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 differentia l modulation of the two types of TNF-R at the surface of PMN and MNC m ight play an important role in the control of peripheral blood cell re sponses to TNF.