The effects of methylnitrosourea (MNU) on natural killer (NK) cell cytotoxicity and cytokine production in rats.

Eight-week-old male Sprague-Dawley rats were exposed to the carcinogen methylnitrosourea (MNU) via gastric intubation at doses of either 10 or 20 mg/kg body wt. Rats were treated once a week for 4 weeks, then once every 2 weeks for 1 month, for a total of 6 treatments. MNU was found to exert no consistent significant immunosuppressive effects in vivo as measured by spleen natural killer (NK) cell cytotoxicity, interleukin-2 (IL-2) production by splenic lymphocytes and prostaglandin E2 (PGE2) production by adherent peritoneal macrophages. In contrast, splenic NK cell cytotoxicity and IL-2 production of MNU-treated rats were actually elevated at several of the later sampling periods. PGE2 production was also elevated in MNU-treated rats in the later sampling periods. Body weights of MNU-treated rats were markedly decreased as early as 4 weeks following the initial MNU treatment. This suppression persisted throughout the study. The most dramatic change in organ weights was seen in the thymus. Thymus weights of all MNU-treated rats were significantly decreased 1 day after treatment and persisted for 4 weeks. By the 60 day sampling period, thymus weights were not significantly different from controls. However, by 120 and 180 days, thymus weights again were significantly lowered in those rats receiving MNU. These changes in thymus weights were accompanied histologically by initial cortical thinning and progressive loss of cortical thymocytes followed by the appearance of hyperplastic and neoplastic cells. It thus appears that the carcinogenic effect of MNU is not related to a depression of the immune surveillance system, at least as measured by NK cell activity.