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Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation
María Emilia Solano, … , Khalil Karimi, Petra Clara Arck
María Emilia Solano, … , Khalil Karimi, Petra Clara Arck
Published March 16, 2015
Citation Information: J Clin Invest. 2015;125(4):1726-1738. https://doi.org/10.1172/JCI68140.
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Research Article Reproductive biology Article has an altmetric score of 8

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

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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.

Authors

María Emilia Solano, Mirka Katharina Kowal, Greta Eugenia O’Rourke, Andrea Kristina Horst, Kathrin Modest, Torsten Plösch, Roja Barikbin, Chressen Catharina Remus, Robert G. Berger, Caitlin Jago, Hoang Ho, Gabriele Sass, Victoria J. Parker, John P. Lydon, Francesco J. DeMayo, Kurt Hecher, Khalil Karimi, Petra Clara Arck

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Figure 4

Progesterone is an upstream modulator of placental Hmox1 expression.

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Progesterone is an upstream modulator of placental Hmox1 expression.
(A)...
(A) RT-PCR quantification in Pgr+/+, Pgr+/–, and Pgr–/– placentas resulting from Pgr+/– matings revealed a significantly reduced Hmox1 expression in Pgr–/– implantations, compared with Pgr+/+ implantations. (B) Effect of progesterone supplementation on gd11.5, gd13.5, and gd15.5 in stressed mice on placental and fetal parameters, compared with stressed mice without progesterone supplementation. From left to right: placental Hmox1 expression assessed by RT-PCR (n = 8 in progesterone supplementation plus stress/n = 9 in stress only), fetal weight and TS development (n = 60/n = 56), placental L/Jz ratio assessed by histomorphology (n = 12/n = 14), CD8+ T cell cytotoxicity (n = 5/n = 7), and CD8+CD122+ T cell frequencies (n = 5/n = 7) analyzed by flow cytometry. Results are provided as relative change induced by progesterone supplementation over stress. Data were calculated by normalizing the values obtained for each variable upon progesterone supplementation to the respective value in stress-challenged nonprogesterone supplemented dams. (C) Levels of serum progesterone on gd16.5 in Hmox1+/+ and Hmox1+/– BALB/c dams. (A and B) Fold change over control expression was calculated using Hprt as housekeeping gene and the ΔΔCt method. The n used in each group and experiment is depicted inside the bars (A and C). Bars represent mean ± SEM. *P ≤ 0.05; **P ≤ 0.01, analyzed by Mann-Whitney U test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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