TUMOR NECROSIS FACTOR INDUCES A NEW REGULATORY CYTOKINE

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Human tumor necrosis factor (TNF) induces a new regulatory cytokine in confluent "aged" cultures of diploid human fibroblasts (FS-4 strain). The induction by TNF of this new cytokine, called interferon-Beta2 (IFN-Beta2), represents an autocrine feedback mechanism regulating cell proliferation. Recombinant human TNF increases cell proliferation in FS-4 cell cultures. This effect can be enhanced further by inclusion of neutralizing antibodies to IFN-Beta in TNF-treated cultures. TNF also exerts an antiviral effect in FS-4 cells which is blocked by antibodies to IFN-Beta. Blot-hybridization analyses of mRNA from TNF-treated cells show that TNF induces the novel IFN-Beta2 gene. Other growth factors (bovine serum and PDGF) also induce IFN-Beta2. These observations raise the possibility that other biological activities of TNF may also be mediated by the induction IFN-Beta2. The cDNA corresponding to the novel 1.3 kb IFN-Beta2 mRNA has been cloned, its nucleotide sequence determined, its amino acid sequence deduced and its polymorphic gene cloned and assigned to human chromosome 7. Experiments are underway to express IFN-Beta2 in E. coli. We shall explore the biochemistry and cellular physiology of the induction of IFN-Beta2 in human fibroblasts by TNF. Key experiments will also be carried out in appropriate murine systems. We propose to complete our studies of the structure of the human IFN-Beta2 mRNA and protein induced by TNF in FS-4 cells and to determine the molecular basis for the increase in steady-state levels of IFN-Beta2 mRNA in fibroblasts treated with TNF. We shall evaluate whether the increased expression of class I HLA genes in human fibroblasts exposed to recombinant TNF, the decreased lipoprotein lipase activity in TNF-treated murine preadipocytes, and the cytotoxic effects of TNF on some human tumor cell lines and in appropriate murine tumor models may also involve induction of IFN-Beta2. The functional consequences of the various polymorphic forms of the human IFN-Beta2 gene and the cell-type specificity of its expression in response to TNF will also be explored. These studies are likely to provide insights important to the use of biological response modifiers such as TNF and IFN-Beta2 in the clinic against neoplastic diseases.