Nonspecific stimulation of the maternal immune system. II. Effects on gene expression in the fetus.
BACKGROUND
Maternal immune stimulation reduces malformations caused by chemical teratogens. Mechanisms for this effect are not known. Altered expression of regulatory molecules (e.g., transforming growth factor [TGF-beta], tumor necrosis factor-alpha [TNF-alpha]) has been reported in fetuses from immunostimulated mice, which may affect gene expression. Expression of selected genes that function to control proliferation, differentiation, or apoptosis was evaluated in chemical-exposed fetuses, with or without maternal immunostimulation.


METHODS
Ethyl carbamate (urethane) was given to pregnant ICR mice on day 10 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 interferon-gamma (IFN-gamma).


RESULTS
Maternal immunostimulation with interferon-gamma (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/apoptotic genes bcl2alpha, bcl2beta, pkCalpha, and p53 in fetal heads. Immune stimulation with IFN-gamma-normalized expression of bcl2alpha, bcl2beta, and pkCalpha to control levels. Urethane also decreased the ratio of expression of bclalpha/p53, bclbeta/p53, and pkCalpha/p53, while maternal injection with IFN-gamma restored these expression ratios to control levels. Maternal immunization with FCA also significantly increased bcl2alpha/p53, bcl2beta/p53, and pkCalpha/p53 gene expression ratios.


CONCLUSIONS
These results suggest that (1) the maternal immune system may possess heretofore unrecognized regulatory activity in fetal development, and (2) protection against urethane-induced cleft palate may be mediated through maternal immune regulation of fetal gene expression.
Sharova
L
L
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0442, USA. ludmila@vt.edu
Sura
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Smith
B J
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Gogal
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Sharov
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Ward
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Holladay
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D000014:Abnormalities, Drug-Induced / Q000235:genetics / Q000517:prevention & control*; D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D002972:Cleft Palate / Q000139:chemically induced / Q000196:embryology / Q000517:prevention & control*; D005314:Embryonic and Fetal Development / Q000187:drug effects / Q000235:genetics; D005260:Female; D005326:Fetal Proteins / Q000235:genetics; D005528:Foot; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D019254:Genes, bcl-2; D016158:Genes, p53; D007267:Injections; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy / Q000276:immunology*; D011493:Protein Kinase C / Q000235:genetics; D051571:Protein Kinase C-alpha; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics; D047488:Retinoid X Receptors; D013723:Teratogens / Q000633:toxicity*; D014157:Transcription Factors / Q000235:genetics; D014520:Urethane / Q000633:toxicity*
D000276:Adjuvants, Immunologic; D005326:Fetal Proteins; D007527:Isoenzymes; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013723:Teratogens; D014157:Transcription Factors; D014520:Urethane; D007371:Interferon-gamma; D005620:Freund's Adjuvant; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha