Immunosuppressive mechanism of 2-Amino-3-methylimidazo[4,5-f]quinoline

Abstract

The effects of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a food- borne mutagen/carcinogen, on immune responses and the mechanism of T cell- mediated immunosuppression by IQ were studied. The suppressive effects of IQ on T - dependent antibody response to sheep red blood cells in vivo and lipopolysaccharide -induced lymphoproliferative response in spleen cell cultures were examined. The IQ also significantly inhibited spleen cell proliferation in response to T - cell mitogenic lectins such as concanavalin A or phytohemagglutinin. Lymphoproliferative response by phorbol 12-myristate 13-acetate and ionomycin activation was inhibited by IQ. It was also found that the cell proliferation stimulated by alloantigens was suppressed by the carcinogen as measured by mixed lymphocytes response (MLR). The secretion of interleukin 1 and nitric oxide production in peritoneal macrophages were suppressed by IQ in a dose-related manner. These results suggest that IQ suppresses the humoral- mediated, the cell-mediated, and the nonspecific immune responses. In order to characterize the biochemical mechanism by which T cell-mediated immune response is suppressed by IQ, the temporal addition studies, in which the carcinogen was added at different time intervals after stimulation of spleen cells by the mitogen, were performed. It was examined whether lymphoid cells express differential sensitivity to IQ at different stages of cellular maturation / differentiation. An inverse relationship was observed between the time of IQ addition with respect to mitogen stimulation and the inhibition of proliferation. The IQ also inhibited cell cycle progression from $G_0/G_1$ to S phase and the cell cycle transition from S to $G_2$/M phase was not perturbed by IQ. These results are consistent with the temporal addition studies suggesting that cells are most susceptible to IQ inhibition at the time of activation. These data further suggest a highly selective mechanism of immunosuppression by I...