1. The Role of TNF-α in Pregnancy

Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. It is produced by macrophages during inflammation and can also be activated by the endotoxin lipopolysaccharide (LPS). TNF-α controls the growth of normal and neoplastic cells, has a profound effect on the expression of genes related to cell differentiation, and influences the function of different cells.

TNF-α has been shown to play a role in the pathogenesis of various inflammatory diseases, such as rheumatoid arthritis, Crohn’s disease, spondyloarthropathies, psoriasis, systemic lupus erythematosus (SLE) or antiphospholipid syndrome, as well as in atherosclerosis, diabetes mellitus, and metabolic syndrome [1]. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development [2]. It was also shown that increased levels of TNF-α are associated with pregnancy loss [3] and preeclampsia [4].

The mother-fetus interaction requires a perfect synergy between the maternal immune system and inflammatory responses, which allows for the immune adaptation of the fetus and, at the same time, maintains immune responses at a level that confers protection from potential infections.

TH1 and TH2 cytokine homeostasis allows for embryo implantation and normal pregnancy outcomes. At the early stages of normal pregnancy, Th1 pro-inflammatory cytokines are necessary for the stimulation of new vessels for successful embryo implantation [5]. However, prolonged exposure to Th1 cytokines may result in a cell-mediated immune response, which is harmful to the fetus and may cause spontaneous abortion [6].

It was noted at the beginning of the twenty-first century that the expression of Th2 cytokines, the anti-inflammatory interleukin IL10 in particular ^[7][8][9][7,8,9], was increased in normal pregnancy, whereas women after pregnancy loss presented a higher expression of Th1 cytokines [10]. The expression of cytokines, as well as the resulting immune response, may also be the result of cytokine gene polymorphism. Thus, cytokine gene polymorphisms can potentially contribute to the risk of recurrent miscarriage, especially gene polymorphisms associated with pro-inflammatory cytokines such as TNF-α, Il-1, Il-6, and IFNG ^{[11][12][13][14][15]}[11,12,13,14,15]. TNF-α may directly promote tissue damage in pregnancy, as suggested by in vitro studies where TNF-α activated maternal monocytes bound to LFA-1 on placental syncytiotrophoblasts and induced apoptosis [16]. Maternal blood levels of TNF-α during pregnancy increase in direct proportion to the stage of pregnancy, as well as in the postpartum period ^[17][18][17,18].

Increased TNF-α levels have been shown to be associated with a number of adverse effects, such as gestational hypertension and gestational diabetes mellitus (GDM) ^[18][19][18,19]. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function ^[20][21][20,21].

Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. Indeed, literature data suggest that trophoblast-derived factors can induce the differentiation of peripheral blood monocytes into macrophages [22], as well as increasing recruitment and differentiation of inducible regulatory T cells (Treg) [23].

To conclude, the placenta is an immunomodulatory organ that regulates both local (embryo implantation) and systemic immune responses [24]. The highly differentiated syncytiotrophoblast is an integral part of the placenta, and the barrier connecting the placental villi with the maternal blood directly exposes the fetus to maternal cytokines.

Diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, may result in the abnormal release of cytokines and chemokines in syncytiotrophoblasts. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy [25]. Furthermore, early pregnancy placenta has a direct impact on fetal development and the maternal immune system [26]. Homeostasis of pro-and anti-inflammatory cytokines is the subject of interest of many scientific studies. Maintaining this fragile balance between pro- and anti-inflammatory factors is crucial for successful implantation and normal pregnancy outcomes. Recent studies have shown a shift in the cytokine profile of the human placenta in the first trimester of pregnancy towards increased levels of GM-CSF, CCL5, and IL10 in response to increased maternal TNF-α levels, while IL-6 and IL-8 remain unchanged [27].