Tumor necrosis factor (TNF; also termed TNF--alpha or cachectin) is a multifunctional cytokine whose biological activities -- in addition to its demonstrated ability to inhibit tumor growth in animals -- include regulatory effects on the synthess of many cellular proteins, inhibitory or stimulatory actions on cell growth, and inhibitory actions on the replications of viruses. Our long-term goal is to obtain a better understanding of the physiological, pathophysiological and host defense functions of TNF, and to elucidate the molecular mechanisms of its important actions. Our studies should also help to better understand the potential and the limitations of TNF as a biological response modifier and antitumor agent. In our present proposal we are seeking a better understanding of TNF's ability to act either as a mitogenic agent or cell growth inhibitor in cultured cells. We shall analyze controlled, standardized conditions. In analyzing TNF's growth-promoting activity in human and murine fibroblasts we shall attempt to determine whether the mitogenic action (a) is due to a direct activation cellular functions promoting quiescent cells to enter and traverse the cell cycle, (b) is due to an induction of cellular responsiveness to extraneous growth factors, and/or (c) occurs via the release of other autocrine growth factor(s) by target cells. In parallel, we shall analyze TNF's ability to alter the expression of some cellular genes implicated in the regulation of cell growth and differentiation. Specifically, we shall analyze mechanisms whereby TNF produces activation of the proto-oncogenes c-fos and c-myc, and of the gene for a secreted protein provisionally termed interferon (IFN)-beta2/BSF-2, and we shall try to determine how the activation of c-fos, c-myc and the IFN- beta2/BSF-2 genes may be related to TNF's ability to stimulate or inhibit cell growth.
