Elevated Serum Level of IL-35 Associated with the Maintenance of Maternal-Fetal Immune Tolerance in Normal Pregnancy

Abstract

ObjectivesIL-35 is a novel inhibitory cytokine. In this study, we investigate the serum levels of inhibitory cytokines IL-35, IL-10 and TGF-β in both normal pregnancies and non-pregnant females, and whether IL-35 is associated with the pathogenesis of recurrent spontaneous abortion. We also try to elucidate the relationships of IL-35 with estrogen and alpha-fetoprotein (AFP).MethodsThe levels of IL-35, IL-10, TGF-β, estradiol (E2), unconjugated estriol (uE3) and AFP were analyzed in 120 normal pregnancies, 40 women suffering recurrent spontaneous abortion, 40 postpartum healthy women and 40 non-pregnant women by enzyme-linked immunosorbent assay (ELISA). The correlations between inhibitory cytokines, estrogen and AFP were assessed with the Spearman rank correlation coefficient.ResultsData are expressed as median and percentiles (Q1, Q3).The level of serum IL-35 in normal pregnancies was significantly higher than that in non-pregnant women [333.6 (59.32, 1391) pg/mL vs. 123.9 (8.763, 471.7) pg/mL; P < 0.001]. A significantly higher level of TGF-β was observed in the first trimester only as compared to non-pregnant women [473.4 (398.0, 580.5) pg/mL vs. 379.7 (311.0, 441.3) pg/mL, P < 0.01]. The difference in serum IL-10 level between pregnant women and non-pregnant women was not significant [8.602 (5.854, 12.89) pg/mL vs. 9.339 (5.691, 12.07) pg/mL; P > 0.05]. The level of serum IL-35 in recurrent spontaneous abortion was significantly lower than that in normal early pregnancy [220.4 (4.951, 702.0) pg/mL vs. 386.5 (64.37, 1355) pg/mL; P < 0.05]. The higher IL-35 level in first trimester pregnant women correlated with E2 (r = 0.3062, P < 0.01) and AFP (r = 0.3179, P < 0.01).ConclusionSerum levels of IL-35 increased in normal pregnancy and decreased in recurrent spontaneous abortion. Increased IL-35 correlated with estrogen and AFP levels in early pregnancy. IL-35 is becoming recognized as an active player in the maintenance of a successful pregnancy, but this is not the case for IL-10 or TGF-β.

Associations of maternal oestradiol, cortisol, and TGF‐β1 plasma concentrations with thyroid autoantibodies during pregnancy and postpartum

“…To our knowledge, this is the only study to have explored TGF‐β1 concentrations in the same cohort of women during pregnancy and postpartum. In a study of 120 normal pregnancies, first trimester plasma TGF‐β concentrations were greater than those in non‐pregnant women while when normal pregnant women were studied in different cohorts at each trimester of pregnancy and on the day of delivery, TGF‐β1 concentrations were greater in all groups as compared to non‐pregnant control subjects, whereas there were no statistical significant differences among the three trimesters and the day of delivery . In a cross‐sectional study where different cohorts of pregnant women were studied in many different time points (from 10th to 38th gestational week), TGF‐β1 concentrations during pregnancy were higher at all time points when compared to non‐pregnant women and decreased along pregnancy .…”

“…In a study of 120 normal pregnancies, first trimester plasma TGFβ concentrations were greater than those in non-pregnant women while when normal pregnant women were studied in different cohorts at each trimester of pregnancy and on the day of delivery, TGF-β1 concentrations were greater in all groups as compared to non-pregnant control subjects, whereas there were no statistical significant differences among the three trimesters and the day of delivery. 19,20 In a cross-sectional study where different cohorts of pregnant women were studied in many different time points (from 10th to 38th gestational week), TGF-β1 concentrations during pregnancy were higher at all time points when compared to non-pregnant women and decreased along pregnancy. 21 However, in another study of different cohorts of pregnant women, TGF-β1 concentrations in mid (16-18 weeks) and late pregnancy (>37 weeks) were greater than non-pregnant women, while its concentrations increased significantly from mid to late pregnancy.…”

“…Among the three known isoforms of TGF‐β present in human serum, TGF‐β1 is the isoform most commonly found in human tissues . Maternal plasma TGF‐β concentrations are greater during pregnancy than in non‐pregnant state but there is no consensus on its quantitative evolution during pregnancy and postpartum …”

“…17,18 Maternal plasma TGFβ concentrations are greater during pregnancy than in non-pregnant state but there is no consensus on its quantitative evolution during pregnancy and postpartum. [19][20][21][22] Increased oestradiol concentrations during pregnancy enhance Th2 responses. 23 Oestrogens induce the decrease of IL-17 production in experimental allergic encephalomyelitis while they inhibit Th17 differentiation and disease progression via oestrogen receptor α (ERα) in T cells.…”

Vitamin D, autoimmunity and recurrent pregnancy loss: More than an association

“…30 When compared to women in normal pregnancies, women suffering from recurrent spontaneous abortion were shown to have drastically deceased IL-35 levels in addition to other anti-inflammatory cytokines.…”