Opposite effects of the maternal immune system activated by interleukin-1beta vs. PSK and OK432 on 5-azacytidine-induced birth defects.

Effects of stimulation of the maternal immune system on abnormal pregnancy induced with 5-azacytidine (5ACDR) administration at embryonic day 7.5 (E7.5) were examined in mice treated with recombinant interleukin 1beta (IL-1beta) at E6.5 (5ACDR + IL-1 at E6.5) or E9.5 (5ACDR + IL-1 at E9.5), OK432 (5ACDR + OK432) at E7.5 or PSK (5ACDR + PSK) at E7.5. Embryos from these dams were examined at E13.5. The frequency of dead and malformed embryos and number of malformations on each embryo increased in the 5ACDR + IL-1 at E6.5 groups compared with the 5ACDR-alone group. Adverse pregnancy outcomes in the 5ACDR + OK432 and 5ACDR + PSK groups were less frequent than in the 5ACDR-alone group. The frequency of exencephaly, facial cleft, eye anomalies (micro- or anophthalmos), and micrognathia significantly increased in the 5ACDR + IL-1 groups, in contrast, that of exencephaly decreased in the 5ACDR + OK432 and 5ACDR + PSK groups compared with the 5ACDR-alone group. The phagocytes on the exencephalic surface drastically increased in the 5ACDR + IL-1 groups, and they often appeared to ingest the migrating neuroepithelial cells. Such findings, however, were rarely observed in the 5ACDR-alone, 5ACDR + OK432 and 5ACDR + PSK groups. Thus, administration of IL-1beta to the abnormal pregnant dams increased the mortality and severity of the malformations in the embryos caused by 5ACDR, whereas PSK or OK432 decreased them. These results suggest that the different modes of activation of the maternal immune system may exert alternative or opposite effects on teratogenic pregnancy.