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Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation.
- Source :
-
Journal of Clinical Investigation . Apr2015, Vol. 125 Issue 4, p1726-1738. 13p. - Publication Year :
- 2015
-
Abstract
- Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered CD8+ T cell response, as evidenced by a reduction of tolerogenic CD8+CD122+ T cells and an increase of cytotoxic CD8+ T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of CD8+ T cells revealed that progesterone suppresses CD8+ T cell cytotoxicity, whereas the generation of CD8+CD122+ T cells is supported by Hmox1 and ameliorates fetal-growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies. [ABSTRACT FROM AUTHOR]
- Subjects :
- *ANIMAL experimentation
*BIOLOGICAL models
*BLOOD circulation
*DRUG design
*CLINICAL drug trials
*FETAL growth retardation
*FETAL malnutrition
*FETUS
*GENES
*MEMBRANE proteins
*MICE
*NOISE
*OXIDOREDUCTASES
*PLACENTA
*PREGNANCY complications
*PROGESTERONE
*RNA
*PSYCHOLOGICAL stress
*T cells
*FETAL development
*DNA methylation
*PREVENTION
*PSYCHOLOGY
*THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 125
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 109779589
- Full Text :
- https://doi.org/10.1172/JCI68140