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 IL-35 in the maintenance of immune tolerance during pregnancy.
IL-35, identified in 2007 is a major immunosuppressive and anti-inflammatory cytokine along with IL-10 and TGF-β.
IL-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. IL-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.
IL-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.
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, report increased serum levels of IL-35 and TGF-β during the first trimester of pregnancy. However, in the second and third trimesters of pregnancy the authors observed an increase of IL-35 levels only. 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 IL-35 levels in recurrent spontaneous abortion was significantly lower when compared to that in normal early pregnancy.
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.