Alterations of rat natural killer (NK) cell cytotoxicity and cytokine production by 3-methylcholanthrene (3-MC)

The carcinogen 3-methylcholanthrene (3-MC) was found to exert immunosuppressive effects both in vitro and in vivo in this study. Spleen cells from 8-week-old male, Sprague-Dawley (S-D) rats exposed to 1, 10 or 100 micrograms/ml 3-MC in vitro for 18 h exhibited a dose-dependent decrease in natural killer (NK) cell cytotoxicity against the YAC-1 tumor target cells in a 4 h 51Cr-release assay. Peritoneal macrophage production of prostaglandin E2 (PGE2) was significantly decreased at all three 3-MC concentrations following a 24 h exposure in vitro. No effect of 3-MC on splenic interleukin-2 (IL-2) production was observed. A separate group of rats was inoculated with a single subcutaneous dose of 5 or 10 mg 3-MC and cytotoxic activity of spleen NK cells was examined at 1, 2, 3, 7, 14, 21, 28, 60, 120 and 180 days after the 3-MC injection. Natural killer cell cytotoxicity was suppressed as early as 24 h after 3-MC injection and persisted up to 21 days. This decrease in NK activity was accompanied by a decreased production of splenic interferon and elevated production of PGE2 by peritoneal macrophages. Natural killer cell cytotoxicity was elevated in the 3-MC-treated rats at 28 and 60 days post-treatment. At 120 and 180 days post-3-MC treatment, when the rats were bearing palpable chemically-induced tumors, NK activity was again significantly depressed. In addition, 3-MC-induced tumors were surgically removed and cultured in vitro. Supernatants from these tumor cell lines were shown to markedly inhibit NK cytotoxicity when tested in vitro. Preliminary results indicate that this inhibition may be mediated by prostaglandins.