Interactions of Tumor Necrosis Factor, Interferon and Interleukin-1 in Cell Killing

Summary

Modulation of cell vulnerability to tumor necrosis factor (TNF) and lymphotoxin (LT) by leukocyte-produced cytokines was examined. Inhibitors of RNA and protein synthesis sensitize cells to the cytotoxic effect of the two cytotoxins (CTXs). The effectivity of killing of such sensitized cells is, however, largely decreased in cells which have been treated for a few hours with crude preparations of the CTXs in absence of the inhibitors. Fractionation of the crude preparations revealed that the cytokines inducing resistance to cytotoxicity of the CTXs are the CTXs themselves and interleukin-l (IL-l). Effective resistance can also be induced with phorbol diesters. On the other hand, IFN-γ increases the effectiveness of cell killing by the CTXs. Modulation of sensitivity to TNF by these agents may in part be explained by their effect on TNF receptor expression: IL-1, the CTXs and phorbol-diesters down-regulate the receptors to TNF while IFN-γ induces an increase in the TNF receptors. However, besides receptor down-regulation additional mechanisms seem to contribute to the resistence since following removal of IL-1, CTXs or phorbol-diesters from treated cells and recovery of the receptors to TNF the cells still exhibit decreased vulnerability to killing by the CTXs.