The role of Interleukin-18 in recurrent early pregnancy loss

• Published in: Journal of reproductive immunology Vol. 148; p. 103432
• Main Authors: Löb, Sanja, Ochmann, Beate, Ma, Zhi, Vilsmaier, Theresa, Kuhn, Christina, Schmoeckel, Elisa, Herbert, Saskia-Laureen, Kolben, Thomas, Wöckel, Achim, Mahner, Sven, Jeschke, Udo
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01-11-2021
• Subjects: Abortion, Habitual - immunology; Adult; Biomarkers - metabolism; Decidua - immunology; Female; First trimester placenta; Humans; Interleukin-18; Interleukin-18 - genetics; Interleukin-18 - metabolism; Placenta - immunology; Pregnancy; Pregnancy Trimester, First; Recurrent miscarriage; Spontaneous miscarriage; Up-Regulation; Young Adult; Recurrent miscarriage; Interleukin-18; First trimester placenta; Spontaneous miscarriage
• DOI: 10.1016/j.jri.2021.103432
• EISSN: 1872-7603
• ISSN: 0165-0378

•Interleukin-18 (IL-18) can induce either Th1 or Th2 immune response depending on the local cytokine environment.•The TaqMan® Human Cytokine Network Array was carried out with placental tissue of patients with healthy pregnancies and recurrent miscarriage in order to investigate differences in IL-18 mRNA expression.•Gene expression analysis revealed a 4,9-times higher expression of IL-18 in recurrent miscarriage patients when compared to the control group..•IL-18 protein expression was investgated in the placenta of patients with healthy pregnancies, spontaneous and recurrent miscarriage.•A significant upregulation of IL-18 in the decidua was restricted to patients with recurrent miscarriage and therefore might be interesting as a diagnostic marker.
A successful pregnancy is a unique and complex immunological state. Cytokines seem to be crucial for the implementation of a tolerogenic environment at the feto-maternal interphase towards the semi-allogenic fetus. Importantly, the switch from a Th1- to a Th2 cytokine profile might play a key role. Interestingly, Interleukin-18 (IL-18) can induce either Th1 or Th2 immune response depending on the local cytokine environment. Therefore, this study investigates the expression of IL-18 in early pregnancy loss.
The TaqMan® Human Cytokine Network Array was carried out with placental tissue of patients with healthy pregnancies (n = 15) and recurrent miscarriage (n = 15) in order to investigate differences in IL-18 mRNA expression. Immunohistochemical staining was applied to examine the IL-18 protein expression in the syncytiotrophoblast and decidua of healthy pregnancies (n = 15), spontaneous (n = 12) and recurrent miscarriage (n = 9). The characterization of IL-18 expressing cells in the decidua was evaluated by double-immunofluorescence. Correlation analysis between IL-18 protein expression and clinical data of the study population was performed via spearman correlation coefficient.
Gene expression analysis revealed a 4,9-times higher expression of IL-18 in recurrent miscarriage patients. IL-18 protein expression was significantly upregulated only in the decidua in the recurrent miscarriage group (p = 0.031). We did not observe significant changes of IL-18 protein expression in spontaneous miscarriage specimens when compared to healthy controls (p = 0.172). Double-immunofluorescence identified decidual stroma cells as IL-18 expressing cells. Correlation analysis showed a significant negative correlation of IL-18 protein expression and gestational age in healthy controls (r = -,745, p = 0.034). Also, a positive correlation of IL-18 and maternal age was observed in patients suffering from recurrent pregnancy loss (r =, 894, p = 0.041).
Our results indicate that IL-18 expression might be necessary in early gestation but requires a tight regulation for a successful ongoing pregnancy. In the present study we observed that a significant upregulation of IL-18 in the decidua was restricted to patients with recurrent miscarriage and therefore might be interesting as a diagnostic marker. Further studies need to evaluate the exact pathophysiological mechanisms.