Abstract
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.
Highlights
The role for the two tumor necrosis factor (TNF) receptors in discriminating TNF and lymphotoxin ␣ (LT␣) effects has been studied
The ratio of the two receptors on the cell surface varies among cells, i.e. some cell types have a high proportion of the p75 TNF receptors (TNFRs) versus the p55 TNFR, and vice versa
When assaying for activation of a CMV reporter construct in the human adenocarcinoma cell line SW480-Gal, 500-1000-fold higher concentrations of LT␣ were required to obtain an effect similar to that induced by TNF
Summary
The role for the two tumor necrosis factor (TNF) receptors in discriminating TNF and lymphotoxin ␣ (LT␣) effects has been studied. These data indicate that the difference in specific activity between TNF and LT␣ in Fs4 and KYM-1 cells cannot be explained by the differences in affinities of LT␣ and TNF to the p55 and p75 TNFRs. Differences in the Rate of Dissociation of TNF and LT␣ from the p75 TNFR—The equilibrium binding experiments described above revealed no major differences between TNF and LT␣ which could explain the large differences in biological activity between the cell lines.
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