A study published in PLoS One indicates that normal pregnancy is associated with increased levels of interleukin (IL)-35, whereas recurrent spontaneous abortions are linked to low levels of this cytokine, suggesting the involvement of this cytokine in the maintenance of immune tolerance during pregnancy.
Pregnancy is a major challenge for the maternal immune system. The foreign antigens expressed by the fetus can even stimulate the immune system. In this complex immunological dilemma, the maternal immune system actively responds to fetal antigens with the help of endocrine pathways.
Regulatory T cells (Treg) play an important role in maintaining immune tolerance, inhibiting progression of autoimmune disease and preventing excessive inflammatory response. Additionally, a specific role in the maintenance of fetal immune tolerance has been widely reported for these cells in both humans and mice.
Cytokine pathways are considered to be the major mechanism for immunosuppression of Tregs. Inhibitory cytokines include IL-10, TGF-β and IL-35.
Interleukin-35 identified in 2007 is a major immunosuppressive and anti-inflammatory cytokine along with IL-10 and TGF-β.
Interleukin-35 belongs to the IL-12 family of cytokines, composed of two subunits – p35 and EBI3, which are shared with other IL-12 family members, specifically IL-12 and IL-27. Interleukin-35 is produced mostly by CD4+ Foxp3+ Treg cells, but also by regulatory B cells and tolerogenic dendritic cells.
The cytokine exerts its immunosuppressive and anti-inflammatory effects by up-regulating regulatory T cells, and by inhibiting of both T helper (Th)1 and Th17 immune responses.
Interleukin-35 is implicated in autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, and in the pathogenesis of asthma.
Interleukin-35 is also implicated in cancer growth by enhancing angiogenesis and TGF-β production, and where it is utilized as suppressive mechanism by inhibiting the recruitment of effector anti-tumor T cells and suppressing their function.
In regards to pregnancy, it appears that first-trimester human trophoblast cells express and secrete IL-35, whereas in women with idiopathic recurrent pregnancy loss, IL-35 is lower compared to fertile controls.
Although IL-10, TGF-β and IL-35 are all inhibitory, the extent of their suppression, and of their non-overlapping functions, needs further clarification. There is a general consensus that Tregs increase in decidual tissue, peripheral blood and lymphoid organs during pregnancy and mediate maternal tolerance to the fetus. However, information on the level of serum IL-35 and its potential role in pregnancy remains limited.
In the PLoS One study, Chao-yan Yue, Bin Zhang, and Chun-mei Ying from the Department of Laboratory Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China, investigated the serum levels of inhibitory cytokines Interleukin-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.
The authors demonstrate that inhibitory cytokines Interleukin-35, IL-10 and TGF-β were elevated to different extents during pregnancy, and IL-35 plays an important role in maternal-fetal immune tolerance.
In the first trimester of pregnancy, the increased immunosuppressive factors were mainly Interleukin-35 and TGF-β; in the second and third trimesters of pregnancy the main immunosuppressive factor was IL-35. During recurrent spontaneous abortion, IL-35 decreased significantly.
In early pregnancy, the IL-35 level positively correlated with estradiol (E2) levels, and the authors speculate that this might reflect the effects of estrogens on Tregs proliferation.
On the other hand, serum Interleukin-35 levels in recurrent spontaneous abortion was significantly lower when compared to that in normal early pregnancy.
These results results indicate that increased IL-35 in normal pregnancy may provide immune protection for the fetus, and insufficient IL-35 is involved in the recurrent spontaneous abortion pathogenesis, so IL-35 associated with the establishment and maintenance of maternal-fetal tolerance during a successful pregnancy.
It has been reported that first-trimester human trophoblast cells expressed and secreted interleukin-35, which might be of benefit to the suppressive capacity of maternal immune cells. In women with history of idiopathic recurrent pregnancy loss, IL-35 was found to be significantly lower compared to fertile controls
Thus, this study implicates IL-35 in the maintenance of immune tolerance during normal pregnancy. This is achieved, as specified by the authors, most likely through “Treg augmentation during pregnancy”.
This may also suggest new therapeutic approaches in infertility, miscarriage and/or pregnancy complications.
Source: PLoS One, 2015; 10(6): e0128219
Read more: PLoS One
Updates
2019a
A 2019 study by Jia Liu et al. explored the participation of two main Breg subsets, including IL-10+ Breg (B10) and IL-35+ Breg cells, in maintaining successful pregnancy.
In animal models, the investigators found that both human chorionic gonadotropin (hCG) and IL-35 suppressed the proliferation of mouse splenic B cells. Moreover, IL-35 induced the expansion of both mouse splenic B10 and IL-35+ Breg cells while hCG only mediated the generation of B10 cells.
Moreover, the authors found that, in mice, the activation of STAT1 and STAT3 in B cells caused by IL-35 and the activation of STAT3 caused by hCG were the predominant mechanism of IL-35+ Breg and B10 cells augmentation.
Thus, the authors concluded that their results suggested that hCG and IL-35 induced the amplification of B10 and IL-35+ Breg cells which may play a vital peripheral regulatory role during pregnancy.
2019b
Another 2019 study by Jia Liu et al. demonstrated IL-35 expression in human first-trimester primary trophoblast cells and trophoblast cell line. Of note, the authors also reported a significant upregulation of serum IL-35 level in the first trimester of pregnancies compared with non-pregnant healthy controls.
According to the investigators, their study showed for the first time that IL-35 secreted by trophoblast cells suppressed T cell proliferation and induced the conversion of Tconv cells into iTR35. Noteworthy, a significant increase in the production of inhibitory cytokine IL-10 was observed in Tconv cells induced by IL-35 from trophoblast cells.
Previous studies showed that IL-35 directly suppresses Th1 and Th17 cells, which, in turn, reduces the production of INF-γ and IL-17. In this study, the investigators confirmed that suppression of Tconv cells proliferation was accompanied by a dramatic decrease in the secretion of IFN-γ and IL-17A.
Interestingly, the in vivo studies demonstrated that mice with immunologically spontaneous abortion have lower levels of IL-35 and iTR35 cells at the maternal–fetal interface, and neutralizing anti-IL-35 mAb enhances abortion rates.
The authors concluded that their study suggested that trophoblast cells contribute to maternal–fetal tolerance via IL-35 secretion, which could suppress the proliferation and induce the conversion of decidual Tconv cells into iTR35 at maternal–fetal interface. Thus, these investigators believe that trophoblast cells-derived IL-35 plays a critical role in maintaining a successful pregnancy.
2020
A 2020 study by Anna Slawek et al. demonstrated that the early stages of abortion-prone pregnancy (3 dpc) in mice were characterized by diminished frequency of B cells producing IL-35 at both local and peripheral levels. The authors concluded that their results and the observed lower level of IL-35 in women suffering from recurrent spontaneous abortion suggest that IL-35 may be involved in the maintenance of pregnancy.
2022
A 2022 study by Letizia Lombardelli et al. reported that human trophoblast cells produced IL-35 but not IL-4 or IL-10. The authors found that human first-trimester primary trophoblast cells spontaneously secrete IL-35 and that IL-35 derived from human trophoblast cells might play an important role in the maintenance of maternal–fetal tolerance by polarizing CD4 + T helper cells in Th2-type cells producing IL-35, IL-4, and IL-10 at the embryo implantation site.
Of note, IL-35+, IL-10+, IL-4+ Th2-type cells, which were found to be induced by low concentrations of IL-35 compatible with those produced by human trophoblasts, were exclusively present in the decidua of a successful pregnancy and at the embryo implantation site, suggesting their stringent dependence on trophoblast cells.
Thus, the authors concluded that the proximity of Th cells to IL-35-producing trophoblasts could be the determining factor for the differentiation of IL-35+, IL-10+, IL-4+ Th2-type cells that are crucial for human pregnancy success.
2025
A 2035 review by Arzou B Chalil et al. investigated the contribution of interleukins IL-15, IL-16, IL-17, and IL-35 to the immunopathology of preeclampsia.
Most studies indicated that preeclamptic women exhibited increased serum concentrations of IL-15, IL-16, and IL-17 relative to normotensive controls. In contrast, IL-35, an immunosuppressive cytokine, was reduced, which implies that there is an imbalance between pro- and anti-inflammatory pathways that may contribute to the progression of preeclampsia.
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