Inhibition of the activity of mouse natural killer cells by urethan.

The effect of the carcinogen urethan on the natural killer (NK) activity of spleen cells from inbred A/J mice was studied. Urethan (1 mg/g) inoculated into 6- to 8-week-old A/J mice produced considerable depression of cytotoxic activity of spleen cells against YAC-1 or RL male 1 tumor cells. This effect was biphasic. Initial depression of NK activity was observed 1 day after urethan treatment, reactivity normalized at 4 days, and then a second, more profound depression was seen around 7-8 days, which persisted for 14-18 days. In contrast, lymphoproliferative responses of spleen cells to mitogens were only transiently depressed after urethan treatment and were in the normal range during the second period of marked depression of NK activity. Urethan appeared to have an even more profound effect on NK activity when given to very young mice (5-17 days old). After one or two injections of urethan, very low splenic NK activity was found 6 and 7 weeks later. The carcinogenic effects of urethan were also more striking in these young recipients, with multiple tumors observed in the lungs at the time of cytotoxicity testing. Inoculation of adult urethan-treated mice with the interferon inducer polyinosinic-polycytidylic acid, boosted NK activity to the same extent as seen with normal mice, which suggested that pre-NK cells are resistant to the effects of urethan. The present data agree with the hypothesis that the ability of a chemical to depress NK cell activity is an important factor in its carcinogenic activity.