Tumor necrosis factor (TNF) is a monokine produced by macrophages in response to invasive stimulation. Tumor necrosis factor can induce hemorrhagic necrosis and regression of some tumors in experimental animals and is cytotoxic to tumor cells in culture. TNF may also be responsible for the wasting (cachexia) often observed in chronic disease states including cancer. My goal is to understand how tumor necrosis factor produces its actions in cells. The initiating step in TNF action is binding to membrane receptors. Affinity labeling has identified TNF binding sites in rat liver that are structurally different from those identified on other cells. It is essential to relate specific cellular responses to interaction of TNF with its different binding sites on various target cells. Elucidation of the molecular basis for TNF action will also require the isolation and purification of the TNF receptor. We wish to understand how TNF binding is regulated and transduced into cellular responses. Binding induces cooperative interactions among TNF receptors. Also, receptors are continuously removed from (down-regulation) and added to (up- regulation) the plasma membrane of target cells. Cooperative interactions among binding sites and down- and up-regulation of the TNF receptor will be characterized and related to changes of cellular responsiveness to TNF. Coupling of cytokine-receptor complexes to the membrane cytoskeleton and changes in the phosphorylation state of specific target proteins are two mechanisms through which binding is transduced into biologic actions. The role of these events in TNF action will be characterized.
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