Preparations of lymphotoxin induce resistance to their own cytotoxic effect

Preparations of human lymphotoxins (LT) were effectively cytotoxic to HeLa cells when applied in the presence of cycloheximide (CHI). In the absence of CHI, however, they failed to cause any cell death. Moreover, LT applied in the absence of CHI induced resistance that was reflected in decreased vulnerability to subsequent incubation with LT in the presence of CHI. This induction of resistance to LT, in treating cells with preparations of LT, was quite rapid, reaching its maximal extent within 2 hr of LT application. It could also be observed in cells of other cultured human lines besides HeLa (SV80 and WISH), and the range of LT concentrations at which it was observed was similar to that at which death of cells was induced by LT in the presence of CHI. In fractionating LT preparations on DEAE cellulose, the resistance inducing activity appeared to co-purify with the cytotoxic activity, suggesting that both activities reside in the same molecule. We suggest that LT, or some lymphokines that are formed by lymphocytes concomitantly with the formation of LT, can induce cellular mechanisms that interfere with the cytotoxic activity of LT and that CHI makes the cell sensitive to the cytotoxicity of LT by reducing the activity of these protective mechanisms. This kind of negative feedback regulation in the function of LT might contribute to selectivity in their action.