FUNCTIONAL DISCREPANCIES BETWEEN TUMOR-NECROSIS-FACTOR AND LYMPHOTOXIN-ALPHA EXPLAINED BY TRIMER STABILITY AND DISTINCT RECEPTOR INTERACTIONS

Tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha) are close ly related cytokines which bind with nearly identical affinities to th e same pair of cell surface receptors, p55 and p75TNFR. Therefore it i s assumed that TNF and LT alpha are redundant cytokines. This study, h owever, demonstrates that TNF and LT alpha differ significantly with r egard to their mitogenic and cytotoxic potentials. LT alpha's superior mitogenic effect could be explained by its formation of a more stable trimer. In contrast to the TNF trimer, which disintegrated under phys iological conditions into biologically inactive monomers; the LT alpha trimer remained stable for several days. Accordingly, LT alpha more e ffectively induced fibroblast growth which demands long-term presence of the cytokine. TNF's superior cytotoxicity, which requires only shor t-term impact of the cytokine, could be attributed to a distinct inter action with the human p55TNFR. This was demonstrated in NIH 3T3 cells transfected with the human p55TNFR, where cytotoxicity is mediated exc lusively by the transfected receptor. Although the p55TNFR had virtual ly identical affinities for TNF and LT alpha, as defined by Scatchard analysis, it nevertheless discriminated between binding of each cytoki ne and showed a 200-fold enhanced cytotoxicity mediated by TNF.