Role of cytokines in a physiological course of pregnancy

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Role of cytokines in a physiological course of pregnancy

Larisa Yuryevna Sashnina, Aleksey Gavrilovich Shakhov, Yuliya Yuryevna Vladimirova, Galina Vasilyevna Nikonenko

Abstract

The article presents an overview of scientific data on the role of pro- and anti-inflammatory cytokines, chemokines and costimulatory factors in case of physiological pregnancy. Considerable attention is paid to the participation of cytokines in the regulation of the relationship between mother and fetus. The mechanisms of the inflammatory response at an early stage of pregnancy, which is necessary to ensure implantation and development of the embryo, are considered. In case of a normal course of pregnancy, the cytokine balance shifts towards immunosuppressive Th2-cytokines, which inhibit cellular immunity reactions and stimulate progesterone, chorionic gonadotropin and the production of blocking antibodies.

Keywords: pregnancy, cytokines, immunosuppression,

cytokine pregnancy fetu inflammatory

Physiological pregnancy is characterized by a state of local immunosuppression and adaptive changes aimed at creating optimal conditions for the growth and development of the fetus [1-10]. Structural and functional restructuring in the immune system of the mother's body is associated with natural (physiological) immunodeficiency, which prevents the rejection of a half-foreign fetus [11-13].

Immunosuppression, which is one of the mechanisms for inducing tolerance to fetal alloantigens, is due to a decrease in the activity of macrophages, neutrophils, natural killers, activation of T-suppressors, as well as a change in the balance of cytokines involved in the regulation of the ratio of immunomodulatory and immunosuppressive effects in the endometrium, trophoblast, and subsequently in the placenta [11, 14-19], and providing a physiological level of coexistence of genetically alien organisms of the mother and fetus [20-28].

Cytokines produced by the cells of the lymphomyeloid complex act as autocrine and paracrine regulators (mediators) of the hypothalamic-pituitary system and are involved in the processes of fertilization, implantation and placentation [24, 25; 29-31].

According to the theory of immunotrophism, the success of pregnancy prolongation depends on the balance of pro-inflammatory Th1 (IL-1, IL-2, IL-6, IL-12, TNF-a, IFN-a, IFN-P, IFN-y, chemokines -- IL-8, monocytic chemotoxic factor, etc.) and anti-ininterferons, T-lymphocytes flammatory Th-2/Th3 cytokines (IL-4, IL-10, TGF-P, etc.) [2, 22, 32, 33] that are mediators of intercellular communications and form a multicomponent system of molecular and cellular regulation of the processes of development and functioning of the fetoplacental complex [6, 34, 35].

It has now been established that during a physiological course of pregnancy, the cytokine balance shifts towards immunosuppressive Th-2 cytokines, which inhibit cellular immunity reactions, stimulate the synthesis of progesterone and chorionic gonadotropin and the production of blocking antibodies [2, 36-40].

According to some authors, the initial period of pregnancy is manifested by a temporary inflammatory reaction with an increase in the expression of pro-inflammatory cytokines necessary for implantation and placentation, while neovascularization and blood supply processes in the endometrium are activated, blood vessels are formed to ensure adequate blood supply to the placenta and fetus [29, 41-43].

As it is known, the central mediator of local and systemic inflammatory reactions is IL-1 [29, 44, 45], which is produced mainly by macrophage cells at the stage of their activation, monocytes, fibroblasts and endothelial cells [21, 23, 24]. IL-1 is expressed by the trophoblast at the site of implantation and is involved in the pre- and implantation development of the embryo [46, 47]. At the initial stages of embryogenesis, under the effect of IL-1, an increase in the trophoblast adhesive properties is noted [48]. It should be noted that it selectively activates the processes of synthesis and secretion of protein-peptide and steroid hormones, releasing factors, the concentration of which has a significant effect on the pregnancy course. By enhancing the production of chorionic gonadotropin, the main hormone of pregnancy IL-1 inhibits the secretion of prolactin. Binding of IL-1 to its receptors in the mother's body promotes implantation and development of the fetus, stimulates the proliferation of cells that form the placental barrier.

Glukhova T.N. [21], Veropotvelyan P.N. [29], Xia H. [48] note that IL-1 plays a key role in the formation of humoral and cell-mediated immunity, is the most important monokine that carries out the processes of generation of effector and regulatory cells of the immune system, having a pronounced effect on the differentiation of immunocompetent cells. The change in the level of IL-1 may be the result of the interaction of the immune and endocrine systems.

The studies by C. Dinarello [49] have found that increased secretion of IL-1 can lead to an increase in the concentrations of tumor necrosis factor alpha (TNF-a), interferon-gamma (IFN-y), IL-2, IL-12, which in turn can complicate the pregnancy course, and maintaining this cytokine at a low level is one of the factors contributing to its prolongation.

One of the main cytokines involved in the regulation of the immune response during pregnancy is IL-2, which is synthesized by type 1 T-helpers and, being an inducer of the secretion of immunopotentiating lympho- and monokines, is involved in the formation of both humoral and cellular mediated immune responses [29].

During pregnancy, the site of synthesis and secretion of IL-2 is the syncytiotrophoblast, in which the genes encoding its amino acid sequence are expressed [21, 23]. Khonina N.A. [24], Glukhova T.N. [21] note the ability of IL-2 to affect the trophism of placental cells and activate suppressor cells.

R. Raghupathy [50] believes that the presence of IL-2 is necessary for the processes of placentation, maturation and functioning of the trophoblast. The studies by C. Chan [51] have revealed that an increase in the production of IL-2 can lead to an increase in the production of other pro-inflammatory cytokines and complicate the pregnancy course.

A multifunctional cytokine with pro-inflammatory immunoregulatory properties is tumor necrosis factor-a (TNF-a). Its main producers are mononuclear phagocytes, lymphoid cells and placenta [21]. When exposed to immunocompetent cells, TNF-a induces the expression of major histocompatibility complex antigens, adhesion molecules, stimulates the production of interleukins IL-1, IL-6, colony-stimulating factors and prostaglandin F-2a [23, 24].

According to the results of a study by Ashton S. et al. [52], TNF-a hypersecretion leads to a significant increase in the number of apoptotic trophoblast cells, which may be one of the factors contributing to pregnancy complications. G.T. Sukhikh [53] has found that TNF-a activates natural killer cells (NK cells) capable of lysing the trophoblast.

According to Staszewski-Chavez S. et al. [54] considerable attention is paid to the role of tumor necrosis factor-a in the regulation of placental cell apoptosis. An increase in its concentration induces inhibition of proliferation and apoptosis of endothelial cells, causing a violation of microcirculation in the placental tissue [55].

Type 1 interferons, IFN-a and IFN-P, belong to cytokines that have predominantly depressant effects. The source of IFN-a is NK cells, T- and B-lympho- cytes, dendritic cells, monocytes, macrophages, etc. [56-59].

IFN-a enhances the production of progesterone by corpus luteum, acts as an inducer of cortisol and chorionic gonadotropin during pregnancy and simultaneously blocks the synthesis of prostaglandin F2a, which determines the physiological development of pregnancy, prolonging the processes of implantation and placentation of the zygote [21, 47]. Possessing a pronounced immunoregulatory effect, it increases the cellular cytotoxicity of T-lymphocytes and NK cells and inhibits the proliferative activity of lymphocytes [58, 59].

IFN-P is synthesized by fibroblasts and epithelial cells [56]. The mechanism of its action is associated with a change in the balance of pro- and anti-inflammatory factors, in particular, suppression of the production of pro-inflammatory cytokines, interleukin-17, IFN-y and an increase in the production of anti-inflammatory IL-10 [60-62].

An important role at the initial stage of implantation and embryonic development is played by IFN-y, which blocks the development of a Th2-type response, inhibits the synthesis of IL-4 and the proliferation of Th2 cells [29]. IFN-y is produced by decidual NK cells and has immunoregulatory, antiproliferative and proapoptotic properties [22, 33, 57, 63, 64].

The molecular mechanisms of action are due to its ability to inhibit trophoblast proliferation and simultaneously suppress the production of GM-CSF, which is its growth factor. In addition, IFN-y stimulates NK cells and cytotoxic T-lymphocytes, forming lymphokine-activated killer cells with the potential to damage the trophoblast and suppress its hormonal function [44].

In the pathological course of pregnancy, hyperfunction of Th1 cells producing pro-inflammatory cytokines, including IFN-y, is possible, which can lead to excessively pronounced inflammatory reactions in the body, especially when infectious agents persist [29].

A low level of IFN-y during pregnancy provides the advantage of suppressor activation over helper activation that prevents fetal rejection [65].

IL-6 along with other placental cytokines is synthesized by T and B lymphocytes, endothelial cells, fibroblasts, monocytes and macrophages, as well as trophoblasts [21, 24, 29, 66]. It has been established that IL-6 produced by trophoblast cells activates the production of choriogonic gonadotropin [67, 68].

On the one hand, together with IL-1 and TNF-a, it implements the rearrangement of the maternal endocrine system, and on the other hand, it controls immune responses in the fetoplacental zone [21].

It should be noted that IL-6, being a regulator of the reactions of the acute phase of inflammation and hematopoiesis, acts as a mediator of protective processes against infection and tissue damage. Under infectious effect, IL-6 induces the synthesis of acute phase proteins in the liver, which contributes to an increase in the level of prostaglandins and premature development of labor [24, 29, 69].

The studies by Margni R., Zenclussen A. [70] have found that IL-6 inhibits the production of IL-1 and TNF-a, thereby providing an anti-inflammatory effect.

A decrease in the production of IL-6 in pregnant women may be one of the pathogenetic factors for the suppression of immunosuppressive reactions and the disruption of the mother's immunological tolerance to fetal antigens [21].

An elevated level of IL-6 is a marker for predicting preterm labor. Veropotvelyan et al. [29] note that IL-6, apparently, activates neutrophil granulocytes, macrophages to the local production of pro-inflammatory cytokines, prostaglandins, NO, which contribute to the process of maturation and opening of the cervix, and similarly IL-1 increases the expression of oxytocin receptors on endometrial cells.

During a physiological course of pregnancy, the IL-8 chemokine produced by macrophages, fibroblasts, endothelial and epithelial cells of the endometrium plays an important role throughout its entire duration. Its synthesis is enhanced under the effect of IL-1 or TNF-y [31, 41, 71, 72], and in the secretory phase of the cycle it decreases under the effect of an increase in the concentration of progesterone.

IL-8 provides angiogenesis and protection of the placental membranes, takes part in the regulation of the maturation of the cervix and the onset of labor [31, 73] causing the migration of neutrophilic granulocytes from the bloodstream and activating the release of collagenase and elastase, enzymes that break down the extracellular matrix produced by cervical fibroblasts [74].

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has a significant importance in reproductive function, including in folliculogenesis, ovulation, endometrial and placental functions [20, 75]. It is produced by endothelial cells, fibroblasts, macrophages and lymphocytes, as well as by epithelial cells of the reproductive tract under the effect of steroid hormones [20].

In addition to regulating the differentiation and functions of immune cells, GM--CSF attracts leukocytes to the endometrium [76]. GM-CSF secreted into the uterine cavity promotes adhesion of preimplantation blastocytes, subsequent growth of the trophoblast and its invasion by increasing the expression of adhesion molecules, enhancing the production of proteases and other cytokines [77, 20].

In the experiments on mice, it has been found that GM-CSF enhances glucose metabolism, proliferation of blastocyst cells and increases the viability of the pre-implantation embryo [78]. In addition, during pregnancy, GM-CSF plays a significant role in the formation of immunotolerance to the fetus through the modulation of the activity of antigen-presenting dendritic cells and macrophages, which determine the severity of the T cell immune response. In the presence of GM-CSF and IL-4, monocytes migrating into the uterine mucosa differentiate into tolerogenic dendritic cells [79].

A decrease in GM-CSF production can affect the function of dendritic cells, shifting their phenotype from tolerogenic to activating Th1 cells and disrupting immunotolerance to the fetus at the early stages of pregnancy, which is observed in infertility and spontaneous abortions [80].

During physiological pregnancy, anti-inflammatory cytokines of the Th-2 type (IL-4, IL-10, TGF-P, etc.) play an important role. They promote placental formation, model trophoblast invasion and differentiation, induce placental proliferation and angiogenesis, and inhibit prostaglandin and monocyte production of pro-inflammatory cytokines [44].

Interleukin-4 is a regulator of growth, differentiation of B-lymphocytes and the process of antibody synthesis, and is found at the mother-fetus border at all stages of pregnancy [20, 22, 81]. IL-4 is produced by activated CD4+ T-lymphocytes (Th2), mast cells, eosinophils, placental cells, maternal decidua, cytotro- phoblast, maternal and fetal endothelial cells. Progesterone also inhibits Th1 responses during pregnancy by increasing IL-4 synthesis. During physiological pregnancy, the level of IL-4 increases, which ensures the normal development of the fetus [22, 44, 81].

Being an antagonist of the differentiation of CD4+ Th1 type and production of Th1 cytokines, IL-4 promotes the polarization of antigen-stimulated naive Th cells into Th2 effector cells, inhibits the activity of macrophages and the synthesis of pro-inflammatory cytokines IL-1, TNF-a, IL-6, then has an anti-inflammatory effect [20].

One of the mechanisms of the positive effect of IL-4 on the development of pregnancy is to ensure, along with GM-CSF, the migration of monocytes from the peripheral blood to the endometrium and their differentiation into tolerogenic dendritic cells, which play an important role in the implementation of the reproductive function [79].

Piccinni M.P. [81], Persson M. [82], Gui J. [83] in the studies on laboratory animals have found that a decrease in the production of IL-4 can lead to spontaneous and induced abortions.

The key cytokine of early pregnancy involved in the formation of the placenta, placental angiogenesis and regulation of trophoblastic invasion is interleukin IL-10, which is produced by trophoblast cells at all stages of pregnancy [31, 41]. Along with this, IL-10 is produced by subpopulations of T cells (Th1, Th2 and Th17), monocytes, macrophages, dendritic cells, B cells, granulocytes, eosinophils and mast cells, epithelial cells and uterine NK cells. [39, 84, 85].

Experimental studies of White C.A. [86] have found that IL-10 is expressed in the uterus, ovaries and oviducts during the estrous cycle, during pregnancy it is produced by decidual cells and until the middle of pregnancy -- by the placenta. Placenta-specific glycoprotein 18, synthesized by trophoblast giant cells, enhances the synthesis of IL-10 in resident macrophages.

As N.V. Kolesnikova [30] notes, a change in the content of steroid hormones does not affect the amount of IL-10 secreted at the level of the uteroplacental barrier, while an increase in the concentration of pro-inflammatory IL-1P induces its significant increase.

The protective effect of IL-10 on the fetoplacental unit is due to the suppression of the inflammatory response by inhibiting the proliferation of Th1 lymphocytes [34], the synthesis and secretion of pro-inflammatory cytokines (IL-1, IL-6, TNF-a, IFN-y, etc.) by macrophages, chemokines [31, 41, 87] and prostaglandins [3, 31].

IL-10 promotes differentiation of Th-0 cells into Th-2/Th-3 phenotypes and enhances their functional activity. On trophoblast cells, IL-10 increases the expression of HLA-G molecules required for successful embryo implantation and maintenance of Th-2 cell activity [3, 88]. At the same time, the studies by Artemyeva [20] have noted that IL-10 belongs to the pleiotropic type of cytokines, since it has both stimulating and immunosuppressive activity.

A decrease in the level of IL-4 and IL-10 contributes to persistent inflammation and, depending on their concentration, gestational age, systemic and local effects, can lead to a range of complications [41].

An important role in the development of the placenta and fetus is played by transforming growth fac- tor-p (TGF-P), which is localized in the placenta, decidual tissue and fetal membranes [29]. The source of TGF-P is the population of decidual NK cells with the CD56 + CD3 phenotype and Th3 cells, monocytes and macrophages. A decrease in its level can cause abortion. [21]

TGF-P has a pronounced inhibitory effect on the processes of DNA synthesis by trophoblast cells and regulates the processes of its invasion, inhibits the synthesis of IL-1, IL-6, IL-8, TNF-P, reduces the production of prostaglandins in the amnion and decidual cells, controls cell growth, adhesion and differentiation of T and B lymphocytes of the mother and fetus, as well as the activity of macrophages. [21, 89].

Glukhova [21] has noted a pronounced ability of the cytokine to regulate repair processes; it potentiates growth-stimulating effects in most mesenchymal cells and simultaneously blocks the growth of epithelial cells. It has been established that TGF-P inhibits proliferative processes in placental cells and lymphocytes, which protects the body of a pregnant woman from malignant trophoblast invasion. TGF-P has a pronounced depressive effect on macrophage and lymphoid cells, directly binding to specific receptors expressed on their surface.

An analysis of literature data on cytokine balance suggests that pro- and anti-inflammatory cytokines play an important role in the preparation of the endometrium for embryo implantation and then in the maintenance of pregnancy. Physiological pregnancy is associated with the dominance of anti-inflammatory cytokines produced by Th2/Th3 T cells and activation of pro-inflammatory mediators synthesized by Th1 cells leads to the breakdown of tolerance and its interruption [21, 29, 90]. However, the studies by a number of authors have noted that the detection of an increased blood content of Th1 cytokines does not always correlate with an unfavorable course and outcome of pregnancy, and conversely, a high level of Th2/Th3 cytokines can be noted in pathology [2, 18, 91]. There are doubts about the need for a clear division of T-helper subtypes, since T cells show a wide variety of «cytokine profiles» [2, 92, 93]. In this case, it is not the deviation of indicators from the norm that is of decisive importance, but the imbalance in the structure of the interaction of interleukins. Assessment of cytokine production during pregnancy makes it possible to clarify the physiological mechanisms that determine the protection of the fetus, to identify markers of cytokine imbalance in pregnancy pathology [30].

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