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- W4234057771 abstract "The pleiotropic cytokine TNF has been implicated in the regulation of many immune and inflammatory responses in vivo, and in addition exerts a wide range of effects on target cells in vitro. However, although two cell surface receptors for TNF have been identified, and their cDNAs cloned, the amino acid residues necessary for the biological activity of TNF have not been characterized. We have therefore constructed derivatives of TNF termed ‘muteins’, in which the first 3 to 7 amino acids of native TNF-α have been replaced, using synthetic cDNA expressed in E. coli. In the present study we compare the effects of native TNF-α and muteins III, IV, V and VI in several different in vitro systems and in one in vivo model. We observed binding to the p75 TNF receptor on Jijoye Burkitt lymphoma cells with native TNF-α and mutein III alone, whereas the p55 TNF receptor on the human epithelioid carcinoma cell line HeLa bound TNF-α, mutein III and mutein V. Muteins IV and VI failed to recognize either TNF receptor. WEHI 164 fibrosarcoma cells were killed by muteins III, V and VI. Human umbilical vein endothelial cells responded to native TNF-α and to muteins III, IV and V, but not to mutein VI, by increasing the surface expression of ICAM-1 antigen and secretion of the cytokines GM-CSF and IL-6. All four compounds were pro-inflammatory in a mouse in vivo model. The results presented in this report confirm that N-terminal amino acids are critical for both receptor binding and biological activity of TNF-α. Amino acid substitution in the N-terminal region of the TNF-α molecule may provide an insight into the mechanism of TNF-α receptor binding, and further elucidate the structural requirements for its biological activity." @default.
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- W4234057771 date "1991-09-01" @default.
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- W4234057771 title "Characterization of the activation domain and post-translational modification of IL-6DBP necessary for induction of acute-phase gene transcription by IL-6" @default.
- W4234057771 doi "https://doi.org/10.1016/1043-4666(91)90050-n" @default.
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