Tumor necrosis factor/cachectin induces a wide variety of biological effects on cell growth and differentiation. This cytokine, synthesized from macrophages and lymphocytes, not only exhibits cytotoxic properties, but also stimulates cell proliferation, and is involved in different pathological conditions including septic shock, rheumatoid arthritis, autoimmunity, HIV gene expression, and cachexia. Although the actions of TNF-alpha appear to be mediated by two specific receptors of Mr of 55,000 and 75,000, little is known about how binding to these two receptors stimulates cells to respond appropriately. Additionally, the precise molecular signal transduction mechanisms that account for the many biological effects of TNF-alpha have not been defined. Other polypeptide growth factors such as EGF, PDGF, insulin, and NGF convey their signals across the cell membrane by stimulating specific phosphorylation events after ligand binding. The TNF receptors share similar extracellular domains with the p75 NGF receptor and several B and T cell surface molecules, however, the intracellular domains are unique and unrelated to any other known protein. We shall test the hypothesis that TNF-alpha action must require additional signalling molecules, in concert with the recently cloned receptors in order to be functionally active. These studies will ultimately elucidate the molecular mechanisms that are responsible for TNF-alpha action during normal and disease states.
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