Human tumour necrosis factors: structure and receptor interactions

Activation of lymphoid and myeloid cells causes the production of factors cytotoxic to various tumour cell types in vitro and in vivo. We have investigated the biochemistry, molecular biology and mechanism of action of two such factors. The factor derived from a myeloid cell line was named TNF-alpha (previously referred to as TNF) and that derived from lymphoid cells named TNF-beta (previously called lymphotoxin). Both proteins were purified from the conditioned media of the human cell lines and sequenced. Structural information revealed that TNF-alpha is 157 amino acid residues long and contains one disulphide bond. TNF-beta is a glycoprotein of 171 amino acids that contains no cysteine residues. Protein sequence information was used to isolate and characterize cDNAs for TNF-alpha and TNF-beta by recombinant DNA methods. The expression of the cDNAs in Escherichia coli made available large quantities of these proteins for biological studies. The two proteins are 31% identical and 52% homologous to each other. The genes for both cytokines are approximately three kilobases in size and are closely linked on human chromosome six. TNF-alpha and TNF-beta both bind to various cell types via a single class of high affinity receptors. On most cells the same receptor is recognized by both cytokines. The receptors for TNF-alpha can be up-regulated by both interferons and lectins. Up-regulation of receptors by interferons is accompanied by synergistic enhancement of the biological response whereas up-regulation by lectins results in an antagonistic response. Besides antiproliferative effects, both cytokines exhibit direct antiviral effects on infection by both DNA and RNA viruses.