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The 60 kDa tumor necrosis factor receptor (TNF&) is regarded as the major signal transducer of TNF-induced cellular responses, whereas the signal capacity and role of the 80 kDa TNFR (TNFR,,) remain largely undefined. We show here that the transmembrane form of TNF is superior to soluble TNF in activating TNFRso in various systems such as T cell activation, thymocyte proliferation, and granulocyte/macrophage colony-stimulating factor production. Intriguingly, activation of TNFRso by membrane TNF can lead to qualitatively different TNF responses such as rendering resistant tumor cells sensitive to TNF-mediated cytotoxicity. This study demonstrates that the diversity of TNF effects can be controlled through the differential sensitivity of TNFRao for the two forms of TNF and suggests an important physiological role for TNFRso in local inflammatory responses.