EVIDENCE FOR A SYNERGISTIC ROLE OF 2 TYPES OF HUMAN TUMOR-NECROSIS-FACTOR RECEPTORS FOR THE LIGAND-DEPENDENT ACTIVATION OF THE NUCLEAR TRANSCRIPTION FACTOR NF-KAPPA-B

Tumor necrosis factor (TNF) is a multipotential cytokine that interact s with a wide variety of cells through two distinct receptors, referre d to as the p60 and p80 receptors. Why there are two distinct receptor s for the same ligand and whether these receptors mediate their signal independently or synergistically is not known. We examined the role o f these two receptors in the ligand-dependent activation of a transcri ptional factor, NF-kappa B, an early response (5-15 min) to TNF in hum an myeloid ML-1a cells. By using receptor type-specific antibodies, th ese cells were found to express almost equal amounts of both receptors . TNF-dependent activation of NF-kappa B could be blocked partially by both anti-p60 and anti-p80, suggesting that TNF mediates its effect i ndependently through the p60 and p80 receptors. In comparison, the act ivation of NF-kappa B by lymphotoxin (LT), which shares receptors with TNF, was completely blocked by anti-p60, whereas anti-p80 had no effe ct. Anti-p60 but not anti-p80 by itself was found to activate NF-kappa B in a dose-dependent manner, but on a molar basis anti-p60 was found to be 100 times less potent than TNF. Interestingly, even though anti -p80 by itself was inactive, it potentiated the effect of anti-p60 syn ergistically, suggesting an interaction between the two types of TNF r eceptor. Thus, overall these results demonstrate that the two forms of TNF receptors could mediate their signal in both an independent and s ynergistic manner and that TNF mediates its signal through both forms of receptors, whereas LT mediates its signal through the p60 receptor.