title: Reduced birth defects caused by maternal immune stimulation may involve increased expression of growth promoting genes and cytokine GM-CSF in the spleen of diabetic ICR mice.
abstract: Maternal immune stimulation in mice decreases fetal abnormalities caused by diverse etiologies. Growth factors produced by activated immune cells were proposed to be key mediators that may exert their effects on placenta or embryo. Diabetes disrupts the secretion of cytokines, which may associate with diabetic embryopathy. Three different methods of maternal immune stimulation that result in approximately equal reduction of diabetic embryopathy were used in the present studies: footpad injection with complete Freund's adjuvant (CFA), intraperitoneal (i.p.) injection with granulocyte-macrophage colony-stimulating factor (GM-CSF), or i.p. injection with interferon-gamma (IFN-gamma). A gene microarray was then used to examine expression of a selected gene panel in splenic leukocytes. We hypothesized that maternal immune stimulation may act by overcoming altered gene expression patterns of immune cells in the diabetic mice, which partially mitigates the teratogenic effect of diabetes. It further seemed likely that a shared profile of splenic gene expression changes induced by the different immune stimulation procedures may be identified and related to reduced teratogenesis. The three procedures produced a common altered gene expression profile. Significantly affected genes included apoptotic and anti-apoptotic genes, and genes controlling cellular proliferation, and likely reflect a state of immune activation. The GM-CSF gene was up-regulated by all three immune stimulation procedures. The protein product of this gene regulates placental development, and was recently associated with reduced cleft palate in immune-stimulated pregnant mice after exposure to urethane. These data suggest that further studies of GM-CSF as mediator of reduced birth defects in teratogen-challenged, immune-stimulated mice are warranted.
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Phase II, Southgate Drive, Blacksburg, VA 24061-0442, USA.
authors.forename: K
authors.initials: K
authors.lastname: Punareewattana
authors.forename: L V
authors.initials: LV
authors.lastname: Sharova
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: D L
authors.initials: DL
authors.lastname: Ward
authors.forename: S D
authors.initials: SD
authors.lastname: Holladay
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D000013:Congenital Abnormalities / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D005620:Freund's Adjuvant / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology; D006133:Growth Substances / Q000235:genetics*; D007114:Immunization / Q000379:methods; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000235:genetics; D010770:Phosphotransferases / Q000235:genetics; D011247:Pregnancy; D025341:Principal Component Analysis; D013154:Spleen / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D006133:Growth Substances; D014157:Transcription Factors; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005620:Freund's Adjuvant; D010770:Phosphotransferases