Distinct Roles of the Two Tumor Necrosis Factor (TNF) Receptors in Modulating TNF and Lymphotoxin α Effects

The role for the two tumor necrosis factor (TNF) receptors in discriminating TNF and lymphotoxin alpha (LTalpha) effects has been studied. TNF and LTalpha were equally mitogenic in Fs4 fibroblasts, which express a high amount of the p55 compared to the p75 TNF receptors (TNFRs). In contrast, TNF was more potent than LTalpha in mediating gene regulation and cytotoxicity in SW480-betaGal cells and KYM-1 cells, which have a high p75/p55 TNFR ratio. Both TNF and LTalpha showed comparable affinities for the two TNFRs. However, in contrast to LTalpha, TNF dissociated rapidly from the p75 TNFR, whereas both cytokines dissociated slowly from the p55 TNFR. Soluble p55 TNFR was much more potent than soluble p75 TNFR in inhibiting TNF cytotoxicity, whereas both soluble receptors moderately decreased LTalpha-mediated cytotoxicity with comparable efficacy. Antagonistic monoclonal antibodies against either TNFR types markedly inhibited TNF effects. However, only the p55 TNFR antagonistic antibody significantly decreased LTalpha-mediated cytotoxicity and cytomegalovirus promoter activation, whereas blocking of the p75 TNFR enhanced the LTalpha effects. These data suggest that whereas the p75 TNFR can both directly propagate TNF signals and "pass" TNF to the p55 TNFR, it attenuates LTalpha and may serve as a decoy receptor for this cytokine.