3-methylcholanthrene: transient inhibition of the lytic step of mouse natural killer cells

Abstract

Female mice belonging to NMRI stock were inoculated neonatally with daily doses of 5 micrograms diethylstilbestrol (DES) or olive oil for the first 5 days after birth and in adult life with 20 or 100 micrograms 3-methylcholanthrene (MCA) or the vehicle tricaprylin only. The cytotoxic activity of spleen natural killer (NK) cells against YAC-1 target cells was studied in a 51Cr release assay at 2, 5, 10, or 15 days after the MCA injection. A dose of 20 micrograms MCA to neonatally olive oil-injected females did not influence the NK activity, whereas an injection of 100 micrograms MCA significantly depressed the NK activity to about half the value seen in controls. This suppression was transient, and the normal level was reached again 15 days after the injection. The depressed NK activity could not be related to humoral or cellular suppressor mechanisms. A study at the single-cell level revealed that the inhibition was due to interference with the lytic step of the NK cell without affecting target-binding capacity. In vitro exposure of spleen cells from MCA-treated animals to interferon fully restored the NK activity. Neonatal DES treatment resulted in a depressed NK activity in adult females to a level about half of that seen in olive oil-injected controls. The NK activity in DES-treated females was not influenced by either 20 or 100 micrograms MCA. The MCA-induced suppression of NK activity was discussed in relation to the earlier reported difference in incidence of MCA-induced sarcomas between DES-treated and control females after they were given 20 micrograms MCA in adult life, as well as in relation to the same incidence in the 2 groups treated with 100 micrograms MCA. The results are compatible with a significant role for NK cells during MCA carcinogenesis and indicate that a possible part of the tumorigenic effect of MCA is its early suppressive effect on NK cell activity.