Nonspecific stimulation of the maternal immune system. II. Effects on geneexpression in the fetus

Background: Maternal immune stimulation reduces malformations caused by che mical teratogens. Mechanisms for this effect are not known. Altered express ion of regulatory molecules (e.g., transforming growth factor [TGF-beta], t umor necrosis factor-alpha [TNF-alpha]) has been reported in fetuses from i mmunostimulaled mice, which may affect gene expression. Expression of selec ted genes that function to control proliferation, differentiation, or apopt osis was evaluated in chemical-exposed fetuses, with or without maternal im munostimulation. Methods: Ethyl carbamate (urethane) was given to pregnant ICR mice on day 1 0 of gestation to induce cleft palate. Before teratogen administration, the immune system of the female mice was stimulated by footpad injection with Freund's complete adjuvant (FCA) or by intraperitoneal injection with inter feron-gamma (IFN-gamma). Results: Maternal immunostimulation with interferons (IFN-gamma) decreased severity of the cleft palate lesion caused by urethane, while FCA decreased both incidence and severity of cleft palate. Gestation day 14 fetuses from urethane-exposed mothers displayed decreased expression of cell cycle/apop totic genes bcl2 alpha, bcl2 beta, pkC alpha, and p53 in fetal heads. Immun e stimulation with IFN-gamma -normalized expression of bcl2 alpha, bcl2 bet a, and pkC alpha to control levels. Urethane also decreased the ratio of ex pression of bcl alpha /p53, bcl beta /p53, and pkC alpha /p53, while matern al injection with IFN-gamma restored these expression ratios to control lev els. Maternal immunization with FCA also significantly increased bcl2 alpha /p53, bcl2 beta /p53, and pkC alpha /p53 gene expression ratios. Conclusions: These results suggest that(1) the maternal immune system may p ossess heretofore unrecognized regulatory activity in fetal development, an d (2) protection against urethane-induced cleft palate may be mediated thro ugh maternal immune regulation of fetal gene expression. (C) 2000 Wiley-Lis s, Inc.