The cytokines IL-1b and IL-18 are upregulated in the placenta of recurrent miscarriage patients

Recurrent miscarriage (RM) remains a relevant clinical problem as in about 50% of the affected women a cause cannot be identified. An exaggerated maternal immune response at the feto-maternal interphase is considered as one important mechanism for unexplained RM. Cytokines seem to play a crucial role to prevent rejection of the semi-allogenous fetus by the maternal immune system. Therefore, this study investigates cytokine secretion profiles in early pregnancy loss. Women with an inconspicuous family and medical history were included in the present study. The TaqMan® Human Cytokine Network Array was applied in order to investigate differences in cytokine mRNA expression in placental tissue of patients with healthy pregnancies (n = 15) and RM (n = 15). The protein expression of IL- 1β and IL-18 was examined by immunohistochemical staining in the decidua of healthy pregnancies (n = 15), spontaneous miscarriage (SM) (n = 18) and RM (n = 15). Double- immunofluorescence was carried out for the characterization of IL- 1β and IL-18 expressing cells in the decidua. Gene expression analysis revealed an overexpression of IL- 1β and IL-18 in RMpatients. IL-18 protein expression was significantly upregulated in the decidua of the RMgroup (p = 0.031). In SM specimens there was no significant difference in IL-18 expression when compared to healthy controls (p=0.172). Immunohistochemical staining showed a significant elevated expression of IL-1β in the decidua of RM (p = 0.01) and SM patients (p = 0.001) in comparison to the control group. Double-immunofluorescence identified decidual stroma cells as IL- 1β and IL-18 expressing cells. IL- 1β expression is significantly elevated in the decidua in both miscarriage groups and IL-18 upregulation is restricted to RM patients. The overexpression of IL- 1β and IL-18 might lead to or may be a result of a pro-inflammatory immune response at the fetomaternal interphase and could consequently induce miscarriage. The secretion of both cytokines is stimulated by the activated inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) and the inhibition of this upstream might be a new therapeutic approach for miscarriage patients