Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation.
J Clin Invest
; 125(4): 1726-38, 2015 Apr.
Article
en En
| MEDLINE
| ID: mdl-25774501
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Placenta
/
Insuficiencia Placentaria
/
Complicaciones del Embarazo
/
Progesterona
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Estrés Psicológico
/
Linfocitos T CD8-positivos
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Desarrollo Fetal
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Hemo-Oxigenasa 1
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Retardo del Crecimiento Fetal
/
Proteínas de la Membrana
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
/
Pregnancy
Idioma:
En
Revista:
J Clin Invest
Año:
2015
Tipo del documento:
Article