Our major goal is to elucidate the mechanisms responsible for the modulation of cell growth and other cell functions by TNF. In view of the many documented cooperative actions of TNF, IFNs and other cytokines on various cell functions, we shall pay special attention to the study of the interactions between TNF, the IFNs (both IFN-alpha/beta and IFN-lambda), interleukin (IL)-1 and IL-6. Most biological actions of TNF and cytokines can be attributed to their ability to modulate gene expression in target cells. In the first part of the proposed studies we shall seek a better understanding of the molecular mechanisms of gene regulation by TNF, using the ability of TNF to induce IL-6 synthesis in human fibroblasts as our main model system. The goals are to gain a more complete understanding of the cis-acting elements and trans-activating factors as well as of the major signal transduction pathways responsible for IL-6 induction by TNF. In the second part of the proposed studies we shall use a set of recently cloned DNAs complementary to mRNAs whose levels are enhanced by TNF treatment in human diploid fibroblasts. The induction characteristics of mRNAs corresponding to these cDNAs will be determined (e.g., kinetics of induction by TNF, tissue specificity of induction by TNF, inducibility by IFN-alpha/beta, IFN-lambda and other cytokines, etc.). We shall also analyze the role of recently identified transcription factors, including interferon regulatory factor-1 and -2 (IRF-1 and 2), in TNF-regulated gene expression and in the synergistic actions of TNF and IFNs on gene expression.
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