Abstract
Sildenafil citrate (SC), a PDE5 inhibitor, a drug for erectile dysfunction (ED) and pulmonary hypertension (PAH), was found to exert a positive effect on pregnancy outcomes when administered intravaginally before conception. In our previous studies, sildenafil increased endometrial thickness and significantly decreased peripheral blood NK cell activity after the intravaginal administration in women with recurrent pregnancy loss (RPL). No data are available to confirm the effect of sildenafil on maternal T cell populations involved in shaping fetal-maternal tolerance and NK cell activity. Thus, the present study aimed to establish if SC influences NKT cells or the axis of Th17/Treg cells and Th1/Th2 cytokine production. Materials and methods: Twenty-one healthy fertile women and twenty-two nonpregnant women with idiopathic RPL were studied. The ELISA method was used to evaluate the production of cytokines, including IL-2, IL-12p40, IL-4, IL-10, IL-6, IL-17, IL-21, TGF-β, TNF-α, and IFN-γ in PBMC culture supernatants before and after supplementation with the physiological concentration of SC. The percentages of NKT (CD56+CD3+CD44+CD161+), Treg (CD4+CD25+FOXP3+) and Th17 (CD4+CD25+IL-17A+) cells were determined with flow cytometry method. Results: Unexpectedly, we found that the PBMCs of patients with RPL produced a significantly lower level of inflammatory cytokines (TNF-α and IL-6) and a higher level of anti-inflammatory cytokines (TGF-β and IL-10). SC significantly decreased IL-6, IL-12 and increased TGF-β cytokine concentration in fertile women. In the case of RPL patients’ PBMCs, SC improved the production of TNF-α and IL-10. Conclusions: Lower concentration of proinflammatory cytokines in idiopathic RPL women compared to fertile women might suggest the exhaustion of the immune system. The emphasized production of IL-10 by SC partially explains the previously observed downregulation of NK cell activity in RPL patients. The immunomodulatory effect of the drug might be utilized in anti-inflammatory therapies and help achieve positive pregnancy outcomes in women with reproductive failure due to a Th1/Th2 imbalance.
Highlights
A positive pregnancy outcome is strictly dependent on maternal immune system tolerance
The basic levels of TNF-α, IL-6 pro-inflammatory cytokines were signifthe concentration of TGF-β was higher in recurrent pregnancy loss (RPL) patients compared to7 of healthy women (Figure 1a,b and Figure 3c, and Table S1 in Supplementary Materials)
We observed a lower concentration of pro-inflammatory cytokines in RPL patients peripheral blood mononuclear cells (PBMCs) compared to fertile women PBMC cultures, which might suggest the exhaustion of the immune system in RPL women
Summary
A positive pregnancy outcome is strictly dependent on maternal immune system tolerance. Several immune mechanisms involving both innate and adaptive immune responses are engaged at the fetal-maternal interface [1]. Recurrent pregnancy loss (RPL) was defined as three consecutive losses earlier than 20 weeks of gestation. Testing women after two losses could spare them another pregnancy failure. The definition was modified by lowering the number of spontaneous losses to two [2]. Unexplained RPL is a growing health problem worldwide. It is estimated that RPL affects more than 1% of the general population of pregnant women, and only half of RPL cases could be explained after medical investigation [2,3]. Each miscarriage increases the risk of the miscarriage to 15% [2]
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