Ligand passing: the 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDa TNF receptor.

L.A Tartaglia,D Pennica,D.V Goeddel

doi:10.1016/s0021-9258(17)46661-0

Abstract

To understand the role of the 75-kDa tumor necrosis factor (TNF) receptor in non-lymphoid cells, the cytotoxic signaling and ligand binding activities of the 55-kDa (TNF-R1) and 75-kDa (TNF-R2) TNF receptors were investigated using agonist and antagonist antibodies specific for the two receptor types. This study indicates that although TNF-R2 can significantly reduce the TNF concentration required for cell killing, the mechanism by which this is accomplished is not through the generation of an intracellular signal by TNF-R2. Instead, TNF-R2 regulates the rate of TNF association with TNF-R1, possibly by increasing the local concentration of TNF at the cell surface through rapid ligand association and dissociation. We propose that other cell-surface receptors, such as the low affinity p75 nerve growth factor receptor, may utilize an analogous "ligand passing" mechanism.

Highlights

TOunderstand the role of the 75-kDa tumor necrosis been developed, and each has been shown to behave as a refactor (TNF) receptor in non-lymphoid cells, the cyto- ceptor-specific agonist and to inducea subset of mTNF activitoxic signalingand ligand binding activities of the55- ties (Tartaglia et al, 1991)
Inhibition of TNF-mediated Cytotoxicity by TNF Receptor- could synergize with signals from TNF-R1 and result in inspecific Antibodies-% help clarify the hnctionalroles of the creased TNFsensitivity
Only signals gentwo TNF receptors, we examined the aboilfiatynti-TNF recep- erated by TNF-R1 result in cell killing, and signals from tor-specific mAbs to inhibit the killingof murine L929 cells by TNF from 293/R2 cells (TNF-R2) play no role

Summary

Introduction

TOunderstand the role of the 75-kDa tumor necrosis been developed, and each has been shown to behave as a refactor (TNF) receptor in non-lymphoid cells, the cyto- ceptor-specific agonist and to inducea subset of mTNF activitoxic signalingand ligand binding activities of the55- ties (Tartaglia et al, 1991). -50% of the cell population (Fig. 4).further addition inhibited by the anti-TNF-R1 antibody (Fig. 6 A ) (differential of mTNF (which has access to TNF-R2) does not enhance this between TNF binding to both receptors simultaneously uersus partial killing, arguing against theexistence of a TNF-R2 sig- TNF-R2 only) and isalso shownin Fig. 6B.

Results

Conclusion