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Current Women’s Health Reviews, 2008, 4, 280-285
Placental Cytokines in the Pathogenesis of Preeclampsia and Hellp Syndrome Andrea Luigi Tranquilli1,*, Alessandra Corradetti1, Stefano Raffaele Giannubilo1, Beatrice Landi1, Francesca Orici1 and Monica Emanuelli2 1
Institute for Maternal and Child Sciences and 2Institute for Biochemical Biotechnologies, Università Politecnica delle Marche, Ancona, Italy Abstract: Preeclampsia and HELLP syndrome are placenta-dependent disorders with both local and systemic anomalies that are responsible for neonatal and maternal morbidity. The cytokines, produced by the placenta in response to local ischemia/hypoxia, may be involved in endothelial activation and dysfunction. The adaptive immune system could play a key role in the etiology of preeclampsia or HELLP by generating a proinflammatory Th1 type immune reaction: the current pathophysiologic hypothesis of preeclampsia is focused on maladaptation of immune responses and defective trophoblast invasion. Also human decidual NK cells recruited at the site of embryonic implantation induce a number of cytokines with potential functions not yet clearly established. We reviewed recent studies on effect of pro-inflammatory cytokines in preeclampsia, as well as on the role of regulatory cytokines and chemokines and discuss evidence that cytokines continue to be part of a paracrine/autocrine regulatory network in the placenta and membranes throughout the different stages of gestation. In addition we reviewed the experimental basis for the possible role of the immune system and proposed the hypothesis that these conditions could be a placental inflammatory response which can lead to a systemic and endothelial dysfunction, resulting in hypertension, proteinuria and pathologies in many organ systems.
Key Words: Preeclampsia, HELLP, placenta, hypertension, pregnancy, cytokines, inflammation. PREECLAMPSIA, CYTOKINES
HELLP
SYNDROME
AND
Hypertensive disorders complicate 6 to 8 percent of pregnancies and are a leading cause of maternal and fetal morbidity and mortality. Among those, preeclampsia is a feature peculiar to pregnancy characterized clinically by hypertension and proteinuria that develops after the 20th week of pregnancy. HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) was firstly described by Weinstein in 1982, as a severe complication of preeclampsia [1]. It is still debated whether HELLP is a distinct entity or a severe form of preeclampsia, of which only the cut-off values change, nevertheless the HELLP syndrome is a lifethreatening complication during pregnancy. Thrombocytopenia and the associated liver disease may be severe, and maternal hepatic complications may progress to the point that transplantation becomes necessary. Current data support the hypothesis that both preeclampsia and HELLP syndrome are placenta-dependent disorders with both local and systemic anomalies that are responsible for very bad maternal and neonatal outcomes, and that a variety of cytokines, produced by the placenta in response to local ischemia/hypoxia, may be involved in endothelial activation and dysfunction that leads to preeclampsia and HELLP.
*Address correspondence to this author at the Institute for Maternal and Child Sciences, Università Politecnica delle Marche at Salesi Hospital, Via Corridoni 11, 60123 Ancona, AN (Italy); Tel: +3907136745; Fax: +3907136575; E-mail:
[email protected] 1573-4048/08 $55.00+.00
Recently, the macroarray analysis allowed to identify 14 cytokines differentially expressed on placentas from preeclampsia and HELLP, and the quantitative RT-PCR confirmed that IL-10, IL-6-receptor and TGF-3 were increased, and CCL18, CXCL5 and IL-16 were significantly decreased in HELLP [2]. Cytokines are small proteins secreted which mediate and regulate immunity, inflammation, and hematopoiesis. They must be produced de novo in response to an immune stimulus and act by binding to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter its behaviour [3]. The predominant producers are helper T cells (Th) and macrophages. Responses to cytokines include increasing or decreasing expression of membrane proteins, proliferation, and secretion of effector molecules [4, 5]. Two functionally distinct subsets of T cells secrete cytokines which promote these different activities. Th1 cells produce IL-2, IFN, TNF and IL-3, GM-CSF which activate Tc and macrophages to stimulate cellular immunity and inflammation and the bone marrow to produce more leukocytes [6]. Th2 cells secrete IL-4, IL-5, IL-6, and IL-10, which stimulate antibody production by B cells. The balance between Th1 and Th2 activity, therefore, may steer the immune response in the direction of cell-mediated or humoral immunity [7, 8]. Their short half life, low plasma concentrations, pleiotropy, and redundancy, all complicate the isolation and characterization of cytokines. Searches for new cytokines are © 2008 Bentham Science Publishers Ltd.
Placental Cytokines in the Pathogenesis of Preeclampsia
now often conducted at the DNA level, identifying genes similar to known cytokine genes. In this review, we also discuss the evidence that cytokines continue to be part of a paracrine/autocrine regulatory network in the placenta and membranes throughout the mid and late stages of gestation. Recent evidence show that the inflammatory cytokines such as tumor necosis factor-alpha (TNF-) and interleukin1beta (IL-1) are involved in endothelial dysfunction [9] so it has been postulated that the adaptive immune system plays a key role in the etiology of preeclampsia by generating a pro-inflammatory Th1 type immune reaction [10]. The placenta is a main component of this inflammatory response as it actively produces a variety of cytokines and immunomodulatory hormones; moreover, placental oxidative stress and aberrant cytokine expression induces an exaggerated maternal systemic inflammatory response to pregnancy [11]. Cytokines have been investigated both in placenta and in blood. PRO-INFLAMMATORY CYTOKINES Among the most important pro-inflammatory cytokines there were the TNF-, IL-6, IL-8, IL-10, IL-12. The TNF-, also known as “cachectin”, is a polypeptide cytokine produced by monocytes and macrophages; it plays a pivotal role in orchestrating innate inflammatory responses in vertebrates [12]. It signals both cell survival and death [13]. It functions as a multipotent modulator of immune response and further acts as a potent pyrogen [14]. The macrophages, present in large amounts in the placental bed of preeclamptic women, are able to limit extravillous trophoblast invasion of spiral arterial segments through apoptosis mediated by the combination of TNF- secretion and tryptophan depletion [15]. Due to its varied actions throughout the immune system, TNF- may play therefore a significant role in the inflammatory component of preeclampsia. Interleukin-6 (IL-6) is a multi-functional cytokine that regulates immune responses, acute phase reactions and haematopoiesis and may play a central role in host defence mechanisms [16]. IL-6 has emerged as a reporter cytokine for intraamniotic infection and obstetric infections [17] and appears to be the most valuable and useful circulating marker of endothelial dysfunction [18]. Benyo et al. investigated the role of different cytokines in preeclampsia, by studying the expression of TNF-, IL-1, IL-1 and IL-6 [19], but found no significant differences in placenta; TNF- only was increased in blood of uterine arteries from preeclamptic women. These data were confirmed only by Heyl et al. [20], their study in vitro on cultured umbilical vein endothelium, indicate that TNF- and IL-1 could not fully explain endothelial activation in preeclamptic patients [17, 21]. The discrepancy with the others studies may be due to the fact that normal placentas can produce more inflammatory cytokines when incubated under low oxygen tension [22].
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Technical bias such as placental sampling or different numbers of patients enrolled in these studies may be confounding factors. We know that the inflammatory cytokines are thought to affect the endothelium in a fashion similar to events reported in preeclamptic women [9, 23], and TNF- levels are higher in the circulation of women with preeclampsia [24]. The placenta, however, is a large heterogeneous organ, so it is very important to sample each placenta in a systematic and unbiased fashion [25]. In fact comparison of cytokine protein levels within a single placenta demonstrated a 3-fold variation among sites that was independent of anatomic location or patient group. Sharma et al., yet using ELISA to detect the levels of TNF-, IL-6 and IL-8 in the blood, had different result [26]. Consistently with other investigators, they found increased circulating concentration of IL-6 as a possible consequence of increased TNF- production [27], and suggested that these cytokines may be used as markers of endothelium dysfunction in preeclamptic pregnancies. Using immunoistological techniques, it has been demonstrated an elevated release of IL-1 and IL-6 from placental tissues obtained from women with uncontrollable preterm labor [28], and these cytokines were shown to be produced from placental endothelial cells, even in the absence of intrauterine infections [29, 30]. Those authors demonstrated that spontaneous delivery at term as well as early-onset preeclampsia or HELLP syndrome are accompanied by an increased intracellular production of IL-6 in fetal monocytes, indicating strong activation of this cell type. Obviously, in case of preeclampsia or HELLP syndrome, such a comparatively high IL-6 production of fetal monocytes indicates an early up-regulation of these immune reactions [31]. These data about the role of IL-6 are consistent with the results found by Strittmatter et al., who investigated the immunological status (IL-6, Interferon-gamma. TNF- and TNF- -receptores p 55/p75) of 32 patients whit HELLPsyndrome and found a significantly higher concentration of TNF- under stimulation of peripheral blood monocytes [32]. ANTI-INFLAMMATORY CYTOKINES The interleukin-10 (IL-10), originally known as cytokine synthesis inhibitory factor (CISF) [33], inhibits the synthesis of certain cytokines like IL-1, IL-2, IL-6, IL-8, IL-12 and TNF- by stimulated macrophages, NK-cells and T-cells. IL-10 also suppresses delayed-type hypersensitivity responses and co-stimulates the proliferation of B cells and their differentiation in to antibody-producing cells, which can express high levels of IgM, IgG and IgA antibodies [34]. There is a general decrease in IL-10 content in cytoplasmic trophoblasts villi in PE compared with placenta from normal pregnancy [35]. IL-10 has been identified as an important cytokine in pregnancy and it may be involved in the maintenance of pregnancy by corpus-luteum maturation and progesterone production [36]. Reports concerning placental cytokine expression in patients with preeclampsia are controversial. Rinehart et al. demonstrated an increased expression of IL-10, IL-1 and
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TNF- in placentas from preeclamptic compared to normotensive patients. This study included 10 patients in total and placental tissue samples were examinated using RT-PCR [21]. Benian et al. also described increased IL-10 protein levels in placentas from preeclamptic patients determined by ELISA [37]. Both studies examined whole placenta tissue sample. A specific immunostaining of trophoblasts for IL-10 and TNF- in placentas from preeclamptic and normal term placentas has been reported by Hennessy et al. [35]. That is consistent with our findings, recently we showed the expression pattern of cytokines and their receptors and the placental villous surface biopsies were taken, in the placentas of pregnancy with HELLP syndrome [1]. The macroarray analysis identified 14 cytokines differentially expressed and PCR confirmed that IL-10, IL-6-receptor, and TGF-3 were increased, whilst CCL18, CXCL5, and IL-16 were significantly decreased, in HELLP. Probably the increased of IL-10R is a compensatory mechanism. The authors demonstrated a significantly reduced villous IL-10 staining in placentas from preeclamptic patients and a lack of staining for IL-10 in stromally placed decidual trophoblast cells and around villi. The results of this study support our findings that there is a significant decrease in IL10 expression and release in preeclamptic placentas [26]. For others, when the balance between the cytokine production from Th-1 type inflammatory and Th-2 is altered with a predominance of the first the IL-10 could not exerts its anti-inflammatory effects on the vascular system [38]. Additionally, Hennessy et al. performed serial sections of placenta and demonstrated a weak correlation between the presence of TNF- and a deficiency of tissue IL-10 in preeclampsia [35]. Placental expression has been proposed as a key element in the T-helper 1 (Th1)/ T-helper 2 (Th2) cytokine bias hypothesis [39]. According to this hypothesis, cytokines like IL-10 that are expressed by Th2 cells suppress the production of pro-inflammatory cytokines by cytotoxic T cells and macrophages and prevent rejection of the fetus in normal pregnancies. This regulatory mechanism seems to be disturbed in preeclampsia, since recent studies show the contribution of Th2 cytokines in maintaining a healthy pregnancy [40, 41]. Consistent with the finding of a reduction of IL-10 production by cytotrophoblast and mononuclear syncytial fragments, our study showed a trend towards increased TNF expression in preeclamptic trophoblasts, but these data lack statistical significance. Other investigators have also reported increased TNF- expression in preeclamptic compared to normal term placentas. It has been suggested that increased placental production of TNF- may contribute to the widespread endothelial dysfunction that characterizes preeclampsia [42]. The authors additionally compared the levels of circulating TNF- in uterine venous and peripheral blood samples from preeclamptic and normal term women. TNF- levels were elevated in peripheral circulation in preeclamptic women but the uterine/peripheral venous TNF ratio was not significantly different [43]. The authors suggested that the source of the increased circulation levels
Tranquilli et al.
of IL-6 in preeclamptic women might be activated leukocytes of the maternal endothelium. Like TNF- and IL-6 also the interleukin-8 is increased in plasma of preeclamptic women [26], it’s a member of the CXC family of chemokines known as CXCL-8 is a major chemoattractant and has been shown to regulate pathological angiogenesis, tumour growth and metastasis [44]. IL-8 and its receptors, CXCR1 and CXCR2, have been observed on endothelial cells [45] and have been shown to play a role in endothelial cell proliferation [46]. IL-1 production has been postulated to be increased in women with preeclampsia due to insufficient changes in the uterine vasculature [22]. Rein et al. [43] also studied IL-1 levels in cytotrophoblast cells and mononuclear syncytial fragment and did not find them increased in preeclamptic placentas. Other investigators, too, failed to detect significant differences of IL-1 production between preeclamptic and normal [19]. Recently also the polymorphs of IL1 gene (IL1-TaqI and IL1-511) and one polymorphism in the IL1RN gene (IL1RN-IVS2), were investigated. The study was performed on a large group: 133 families with either eclampsia, preeclampsia or HELLP syndrome, 101 with preeclampsia only, and 63 with HELLP only, but no significant differences in genotype and allele frequencies were found. IL1 and IL1RN polymorphisms provided evidence for either association or linkage with the risk for preeclampsia/HELLP syndrome, preeclampsia only or HELLP syndrome only [47]. Heyl et al., demonstrated no significant correlations between levels of TNF- or IL-1 and circulating adhesion molecules in the serum of preeclamptic pregnant women. Nor increased serum concentration of ICAM-1, P-selectin and IL-1 were found in their patients, in contrast to in vitro investigations on cultured umbilical vein endothelium [48, 49]. These results would indicate that TNF- and IL-1 can not explain endothelial cell activation, and that their measurement in serum is not useful for the detection of preeclampsia [20]. This study was performed using ELISA test on a good number of patients but the weeks at delivery were significant different between the groups, so was the time at the blood collection. In conclusion, the non critical role of IL-1 in the pathogenesis of HELLP was supported by many studies [50]. Between the cytokines investigated there is also the IL12. It has been reported that serum IL-12 (p40 subunit) concentrations were elevated in women with both severe preeclampsia or HELLP syndrome. In addition, women with severe preeclampsia and HELLP syndrome commonly have detectable concentrations of the IL-12 p40 monomer and were more likely than normal control women to have detectable serum IL-12 p75 dimer [51]. In conclusion the data seems to support the hypothesis that PE and HELLP syndrome could be a placental inflammatory response which leads to a systemic and endothelial dysfunction. CONCLUSION The primary event in preeclampsia has been postulated to be the reduced uteroplacental perfusion as a result of
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abnormal extravillous cytotrophoblast invasion and remodelling of the uterine spiral arteries.
factors involved in stimulating the maternal or fetal nonspecific immune system.
Focal ischemia and hypoxia, deportation of hypoxemic trophoblast cells and abnormal expression of various placental biologic molecules, particularly the cytokines, are thought to lead to widespread dysfunction of the maternal vascular endothelium.
The cytokine elevation in preeclampsia is still discuss in literature, anyway the exactly role and function of every cytokines is not clear, we think that probably they are the one element of a complex network which play an important modulate role during the early stage on trophoblast invasion. Sudden some cytokines as TNF-, IL-6, IL-10, seems to play a central role in the modulations of inflammatory response during pregnancy.
In this review, we discuss the role of cytokines molecules and their receptors, produced at the maternal-fetal interface, of the innate immune system in the pathophysiology of PE and HELLP syndrome. Peter Carmeliet suggested in PE, that angiogenic switch is insufficient, causing endothelial cell dysfunction, vessel malformation or regression or preventing revascularization, healing and regeneration [52]. The ensuing infarction of placenta leads to leakage of increasing amount of placental fragment and cytokines in maternal circulation and an exaggerated systemic endothelial activation as identified in PE. In the last years the molecular biological technologies give us a new approach to examine the ethiology of pregnancy-induced hypertensive diseases. Anyway the exact role of these many molecules in hypertensive disease during pregnancy is unclear, but the data support the hypothesis that the regulation of them production and metabolism is abnormal in women with HELLP syndrome. The data of the recent studies shows that there is a different expression of different type of cytokines and their receptors and the involvement of the cytokines thus supporting the hypothesis of an immunological genesis. These findings suggest that extensive activation of the fetal macrophage/monocyte system is involved in mechanisms inducing spontaneous term delivery and that these immunologic reactions are up-regulated very early in case of preeclampsia [31]. These observations that normal term delivery is already characterized by changes in aspects as intense of fetal monocyte activation as those observed in fetuses born from preeclamptic mothers are in good agreement with observations reported for the maternal non adaptive immune system. Thereby it seems that such a response is already established in normal pregnancy and that the response is exaggerated in preeclampsia [53]. As the investigators found, the elevated amounts of proinflammatory cytokines such as TNF-, IL-6, and IL-12 are detectable in the maternal circulation [54, 55]; intracellular reactive oxygen species are increased and surface antigens (CD11b, CD64, CD14) which are known to be up-regulated on peripheral leukocytes during inflammation are expressed in increased amounts or shed into the maternal circulation (HLA-DR) [54-56]. Such findings support the hypothesis that normal pregnancy itself stimulates a systemic inflammatory response of the maternal nonadaptive immune system, which increases with advancing gestational age and which is extreme in the preeclampsia. For others [31] similar inflammatory reactions of fetal nonadaptive immune system occur in the fetal circulation. But since now, less information exists about
As we know the reports concerning placental cytokine expression in patients with preeclampsia are controversial. Probably that is because probably the authors could not considered the same diagnosis criteria of HELLP or preeclampsia, so often the gestational age of populations studied are not similar and the measurements are made on different type of population. However, given the heterogeneous nature of patients with severe preeclampsia, and the relatively small number of patients enrolled in the studies, care must be advise in extrapolating the findings to all patients with PE or HELLP syndrome. The other critical point that may be determinant for different results obtained in the different studies could be a technical considerations such as placentas sampling, mode of delivery, as well as differences in PCR-RT or ELISA or in vitro cultivation. As most authors used an immunoassay [57], others preferred a bioassay [58], which makes it difficult to compare the several studies. In addiction Kupferminc et al., demonstrated, that an increased of TNF- receptors could prevent the detection of elevated TNF- serum levels [59]. So far, treatment of PE is focused on sign like hypertension, whereas attempts to modify immune responses may be a possibility in the future [60]. These results also show that blocking same of these cytokines we could reduce liver cell apoptosis, indicating that such a strategy may have therapeutic advantages. ABBREVIATIONS ICAM
=
Intercellular adhesion molecole
TNF
=
Tumour necrosis factor
IL
=
Interleukin
IL-R
=
Interleukin-receptor
IFN
=
Interferon
GM-CSF =
Granulocyte macrophage colony stimulating factor
Th
=
T helper
NK
=
Natural killer
TGF
=
Tumor growth factor
CISF
=
Cytokine synthesis inhibitor factor
CD
=
Cluster of differentiation
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Revised: September 29, 2008
Accepted: November 8, 2008
