BIOLOGICAL-ACTIVITIES OF HUMAN TUMOR-NECROSIS-FACTOR-ALPHA AND ITS NOVEL MUTANTS

Biological activities of human tumor necrosis factor-alpha (hTNF-alpha ) and its mutants were compared. In cytotoxicity assay with L929 cells , one mutant, designated as TNF-B, showed 4.5-fold higher activity tha n TNF examined. And TNF-B also increased cytostatic activity and decre ased protein synthesis against U937 cells. In receptor binding assay, TNF-B had almost the same affinity for TNF receptors on L929 cells as hTNF-alpha, But another mutant, TNFarg, markedly decreased the all act ivities of hTNF-alpha and had lower affinity for receptors on differen t types of target cell. These results indicated that the relative acti vity of TNFs to target cells may correlate with their affinity for rec eptors. We also found that TNF-B retained the cytotoxicity of hTNF-alp ha for HEp-2 cells. TNF-B also had two-fold higher affinity than hTNF- alpha for receptors on HEp-2 cells (only carrying hTNF-R55) and lower affinity for receptors on U937 cells (expressing mainly hTNF-R75). The se results suggested that TNF-B might still interact with the human TN F-R55 receptor,but it might largely lose its ability to bind to human TNF-R75. Changes of biological activity of TNFs might be due to an alt ered affinity to the different types of TNF receptor on the target cel ls.