Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system
Adrian Erlebacher, Dorothy Zhang, Albert F. Parlow, Laurie H. Glimcher
Adrian Erlebacher, Dorothy Zhang, Albert F. Parlow, Laurie H. Glimcher
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Article Immunology

Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system

Abstract

We describe a murine model of early pregnancy failure induced by systemic activation of the CD40 immune costimulatory pathway. Although fetal loss involved an NK cell intermediate, it was not due to lymphocyte-mediated destruction of the fetus and placenta. Rather, pregnancy failure resulted from impaired progesterone synthesis by the corpus luteum of the ovary, an endocrine defect in turn associated with ovarian resistance to the gonadotropic effects of prolactin. Pregnancy failure also required the proinflammatory cytokine TNF-α and correlated with the luteal induction of the prolactin receptor signaling inhibitors suppressor of cytokine signaling 1 (Socs1) and Socs3. Such links between immune activation and reproductive endocrine dysfunction may be relevant to pregnancy loss and other clinical disorders of reproduction.

Authors

Adrian Erlebacher, Dorothy Zhang, Albert F. Parlow, Laurie H. Glimcher

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Ovarian mRNA expression of IL-6, IκBα, Socs1, and Socs3 upon systemic CD...
Ovarian mRNA expression of IL-6, IκBα, Socs1, and Socs3 upon systemic CD40 ligation. Whole-ovary mRNA expression levels were determined by real-time RT-PCR. Ovaries were collected from mice on E4 12 hours after treatment with rat IgG or FGK45 (n = 4 mice per group); with FGK45 plus control hamster IgG or FGK45 plus TNF-α–neutralizing mAb’s (n = 5 mice per group); or with rat IgG plus progesterone or FGK45 plus progesterone (n = 4 mice per group). Ovaries were collected on E8 12 hours after injection of rat IgG or FGK45 (n = 3 mice per group). Data represent mean ± SEM. On E4, IL-6, IκBα, Socs1, and Socs3 mRNA levels were increased following FGK45 injection (*P < 0.05; **P < 0.005). These increases were inhibited by TNF-α blockade but not prevented by concurrent progesterone treatment. On E8, FGK45 injection led to upregulated mRNA expression of IL-6 and IκBα, but not Socs1 or Socs3. For ease of graphical representation, transcript levels for IL-6, IκBα, and Socs3 were multiplied by 1,000, 2, and 5, respectively.