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Mpp354200.indd

Accepted: December 16, 2012 Published online: August 15, 2013 Cytokines as Key Players in the
Pathophysiology of Preeclampsia

Department of Microbiology, Faculty of Medicine, Health Sciences Centre, Kuwait University, Safat, Kuwait Key Words
mental pathophysiological feature of this syndrome. Recent Preeclampsia · Cytokines · Pregnancy · T helper 1 · evidence also supports important roles for proinflammatory cytokines in hypertension, proteinuria, and edema which are characteristic features of PE. Abstract
Preeclampsia (PE) is an important, common, and dangerous
complication of pregnancy; it causes maternal and perinatal
Introduction
illness and is responsible for a high proportion of maternal and infant deaths. PE is associated with increased blood The process of pregnancy is besieged by many poten- pressure and proteinuria, with a whole host of other poten- tial challenges, of which one of the most common is pre- tially serious complications in the mother and fetus. The ma- eclampsia (PE), a multisystem disorder unique to preg- ternal syndrome in PE is primarily that of generalized dys- nancy associated with elevated blood pressure (BP) and function of the maternal endothelium, and this generalized proteinuria typically presenting after 20 weeks of gesta- endothelial dysfunction appears to be part of an exagger- tion. Gestational hypertension is the presence of new hy- ated systemic inflammatory response that involves maternal pertension (usually systolic BP >140 mm Hg and/or dia- leukocytes and proinflammatory cytokines. This review ex- stolic BP >90 mm Hg) occurring in the second half of amines evidence that points to a significant role for the ma- pregnancy, while PE is the combination of gestational hy- ternal immune system; inadequate trophoblast invasion of pertension with new proteinuria [1] .
spiral arteries initiates ischemia and hypoxia in the placenta, Worldwide, PE is the most common of the various hy- resulting in an increased release of proinflammatory cyto- pertensive disorders of pregnancy, affecting an estimated kines in the placenta. Placental ischemia and hypoxia also 2–10% of pregnant women [2, 3] . More than 4 million cause the enhanced release of trophoblast microparticles women across the world develop this disorder every year into the maternal circulation which stimulates increased in- [4] , and an estimated 50,000–76,000 women and 500,000 duction of proinflammatory cytokines and the activation of infants die of this condition every year [3] . In fact, PE is a maternal endothelial cells. This activation results in a system- principal cause of fetal morbidity and mortality and ic, diffuse endothelial cell dysfunction which is the funda- causes 15–20% of maternal deaths worldwide [5] .
Department of Microbiology, Faculty of Medicine Health Sciences Centre, Kuwait University is is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Un- ported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribu- tion permitted for non-commercial purposes only.
Defective trophoblast invasion of maternal spiral arteries Release of trophoblast microparticles into maternal circulation Fig. 1. Proposed stages of events in PE.
Symptoms of PE may include edema of the hands and what has been described as ‘a complex, elusive and unpre- face/eyes and weight gain; severe PE may present with dictable disease’ [9, 10] . Indeed, Saito [11] describes PE as headaches, abdominal pain, agitation, decreased urine involving a ‘chaos of theories’. However, intensive re-output, nausea, vomiting, and vision changes. PE is per- search in the last decade has contributed to a better un- haps the most dangerous complication of pregnancy be- derstanding of the pathogenesis of PE. Most investigators cause it has the greatest effect on maternal and infant out- now agree that the basic cause of the diverse maternal comes [3, 6, 7] and is the chief cause of protracted ante- symptoms of PE is a generalized dysfunction of maternal natal hospital stay, induced preterm delivery, and slow endothelium [12] which seems to be a part of a general-growth of infants. Adverse conditions associated with PE ized systemic inflammatory response that involves ma- include maternal multisystem complications such as oli- guria, thrombocytopenia, pulmonary edema, right upper quadrant pain, elevated liver enzymes, and unfavorable placental/fetal outcomes such as abruptio placentae, in- Pathogenesis of PE
trauterine growth restriction, oligohydramnios, and ab-sent or reversed umbilical artery diastolic flow [7] . Thus, The sequence of events in PE is proposed to occur in a wide range of potentially serious fetal and maternal con- two stages: a ‘placental’ stage (or stage 1) and a ‘periph- eral’ stage (or stage 2) [12] . During stage 1, inadequate What induces PE? How is the pathophysiology of PE development of maternal spiral arteries results in a defi- mediated? What are the mechanisms underlying PE-as- cient maternal blood supply to the placenta, bringing sociated hypertension, proteinuria, and edema? These about placental ischemia and hypoxia; this appears to be questions have plagued researchers and clinicians alike, followed by stage 2, consisting of the classic manifesta-even though PE has been known for a long time now. In tions of widespread endothelial dysfunction, hyperten-1916, Zweifel [8] described PE as ‘a disease of theories’ sion, proteinuria, and edema ( fig. 1 ).
presumably because of the innumerable theories and The fetus depends on the blood supply from the moth- speculations put forth to explain the etiopathogenesis of er flowing into placental blood spaces via maternal spiral arteries which are the terminal branches of radial arteries ma of normal pregnant women; levels of STBM were that run from the uterus through the decidua. Spiral ar- shown to be significantly higher in PE [24, 26, 27] . This teries, under normal circumstances, are invaded by pla- led to the hypothesis that STBM is shed into the circula- cental cytotrophoblast cells which replace the endothe- tion of PE patients in higher amounts than in normal lium of these arteries and remodel the vascular wall, pregnancies due to oxidative stress brought about by a causing the blood vessels to dilate [13] and thus better poor blood supply and hypoxia [27] . STBM are made up accommodate the increased blood supply needed by the of products of trophoblast apoptosis [28] and are report-fetus and placenta [14] . On the other hand, in PE, tropho- ed to inhibit the proliferation of endothelial cells in cul- blast invasion of spiral arteries is insufficient, resulting in ture and disrupt the continuity of established endothelial narrower blood vessels [15] which are unable to transport cell monolayers [29] . STBM preparations from PE pla- adequate blood to the placenta which then becomes in- centas are qualitatively not different from STBM prepara- creasingly ischemic in the second half of the pregnancy tions from normal placentas; their ability to induce endo-[reviewed in 16 ]. Thus, shallow trophoblast invasion [17, thelial dysfunction is proposed to be due to higher levels 18] and improper remodeling of the spiral arteries [19, in PE [23, 26, 27] . More interestingly, these microparti-20] are believed to result in abnormal prolongation of hy- cles provoke endothelial cells to release proinflammatory poxia. In addition to placental ischemia, acute atherosis factors [30, 31] and induce maternal leukocytes and en-of spiral arteries adds a further complication. Spiral arter- dothelial cells to produce proinflammatory cytokines [12, ies with poor trophoblast invasion and remodeling also 32] ; this has relevance for the induction of an inflamma-show signs of acute atherosis which includes disruption tory state, which is the focus of this review. In fact, the of the endothelium, fibrinoid necrosis, and leukocytic in- generalized an excessive maternal inflammatory reaction filtration, leading to partial or complete blockage of the seen in PE appears to be associated with an increased re-arteries [21] . This secondary complication aggravates the lease of these microparticles [32] . Also released from the problem of poor blood-conducting ability, resulting in placenta in PE are antiangiogenic factors that may act on hypoxia of the placenta which in turn causes several gross the endothelia of organs such as the kidney, liver, and and histological changes such as infarcts, proliferation of brain, resulting in the production, by damaged endothe-the cytotrophoblast, and outgrowth lesions of the syncy- lial cells, of proinflammatory cytokines [reviewed in 16 ].
tiotrophoblast [22] . Perhaps the most relevant outcome of this damage to the placenta is the shedding of tropho-blast cells and trophoblast microparticles into the mater- PE: An Immune-Mediated Disease?
nal circulation which can be viewed as the beginning of stage 2 of PE [23] .
The placenta has the rather challenging task of main- Stage 2 of this disease was first described by Redman taining a very delicate balance between allowing tropho- and colleagues [24] to be the result of diffuse maternal blast invasion of spiral arteries to take place on the one endothelial dysfunction manifested as endotheliosis of hand and preventing uncontrolled invasion on the other. renal glomerulae, increased levels of components of the Maternal immune cells appear to serve as immunological endothelial extracellular matrix, raised plasma levels of policemen, thwarting an overly robust trophoblast inva-fibronectin and von Willebrand factor, increased vascu- sion; at the same time, an exaggerated immune response lar permeability, enhanced vascular resistance, and plate- may restrain this to the extent that it results in insufficient let aggregation. Furthermore, this generalized endothe- invasion of the arteries and consequently poor vascular lial dysfunction can be attributed to trophoblast mi- remodeling, constricted blood flow, and hypoxia. A role croparticles originating from the ischemic placenta [23, for the immune system has also been shown for the pla-24] .
cental damage seen in PE; increased levels of some com- Microparticles are present in blood circulation even plement components [33] and higher levels of IgG are under normal physiological conditions and can induce found in preeclamptic placentas compared to placentas cell signaling leading to processes like invasion, angio- from normotensive pregnancies [34] .
genesis, and apoptosis; moreover, microparticles are also A role for immunologic effectors is more evident in involved in thrombosis, inflammation, and vascular dys- stage 2 of PE, leading up to widespread endothelial dam- function [25] . Sargent et al. [24] demonstrated the pres- age. Neutrophils are abnormally activated in PE [35] and ence of subcellular trophoblast microparticles [termed this activation has been attributed to immune mecha-syncytiotrophoblast microparticles (STBM)] in the plas- nisms, e.g. inflammatory cytokines produced by T cells. Activated neutrophils could cause vascular damage and these markers and mediators of inflammation in normal interact with platelets and coagulation systems. Clark et pregnancies are significantly lower and similar to those in al. [35] suggest that the activation of neutrophils, and en- dothelial cells and platelet/coagulation activate one an- Toll-like receptors (TLRs) also appear to contribute to other, bringing about a vicious cycle of mutual activation. the induction of PE [49] . TLRs are part of the innate im- In addition to neutrophils, other immune effectors that mune system, and these cell surface receptors recognize appear to play critical roles are cytokines, which are per- evolutionarily conserved pattern-recognition molecular haps the most important initiators and mediators of in- patterns on pathogens. Stimulation of TLRs on monocyte flammation and endothelial dysfunction; thus, a great surfaces elicits the production of several cytokines. Inter-deal of attention has been focused on cytokines produced estingly, a recent study showed that the stimulation of both by the placenta and by leukocytes in the periphery.
TLR4 using low doses of lipopolysaccharide brings about a PE-like syndrome in pregnant rats [49] ; indeed, the ex-pression of TLR4 has been shown to be elevated in inter- Pregnancy, PE, and Inflammation
stitial trophoblast cells of preeclamptic placentas [50] .
Pregnancy has been described as a state of ‘mild, con- trolled inflammation’ [36] , while PE appears to be a state Cytokines and PE
of an exaggerated inflammatory response [37, 38] . Both normal and preeclamptic pregnancies show an increased Substantial evidence has accrued over the years sup- inflammatory response with increasing gestational age porting roles for cytokines in the pathogenesis of PE at [39] . It is suggested that a mild inflammatory response in the early placental stage and in the later systemic stage as a normal, successful pregnancy is actually beneficial to well. Cytokines play critical, essential roles in signaling pregnancy [40] , and that when this inflammatory re- between cells of the immune system, with a prolific range sponse becomes amplified it results in the development of regulatory activities including the recruitment, activa-of PE. Inflammation is necessary during pregnancy, but tion, stimulation, killing, and suppression of immune and at the same time needs to be tightly controlled to prevent nonimmune cells. Interestingly, research in the last two excessive inflammation, and is probably achieved by re- decades has shown that cytokines are also involved in sev- ducing the production of proinflammatory cytokines eral events in pregnancy such as ovulation, implantation, and/or increasing the production of anti-inflammatory placentation, and parturition [51] . Cytokines like granu-cytokines [41, 42] . The abnormal inflammatory response locyte-macrophage colony-stimulating factor (GM-CSF), seen in PE is believed to be caused by the higher levels of colony-stimulating factor-1, IL-3 [52] , and IL-10 [53] STBM shed into maternal blood [28–31, 43] which are contribute to the success of pregnancy, while cytokines suggested to cause endothelial dysfunction primarily via such as TNF-α and IFN-γ have been shown to have harm-the induction of proinflammatory cytokines [12, 23, 24, ful effects on pregnancy [54, 55] . IL-2, TNF-α, and IFN-γ 27, 36] . Many of the symptoms of PE can be attributed to are characteristic of T helper 1 (Th1)-type immunity and an inappropriate or exaggerated activation of maternal induce several cell-mediated cytotoxic and inflammatory inflammatory responses. In addition to the activation of reactions. Th2-type cells, on the other hand, secrete the neutrophils and monocytes, PE is associated with en- Th2 cytokines IL-4, IL-5, IL-6, and IL-10 and are associ- hanced production of phospholipase A2, an important ated with help for humoral immunity [56, 57] . Th2-type mediator of inflammatory reactions [44] , increased ex- immunity is associated with a normal pregnancy, where- pression of cell-surface markers of leukocyte activation, as a strong Th1 reactivity is associated with pregnancy C-reactive protein [45] , activin A [46] , and several in- complications such as recurrent spontaneous miscarriage flammatory cytokines. A recent large case-control study [58, 59] , preterm delivery [60, 61] , and premature rupture showed an association between PE and SEPS1, an inflam- of fetal membranes [62] . In addition to being classified as matory response gene which is proposed to be responsi- Th1 and Th2 cytokines, cytokines can also be classified as ble for the elevated levels of proinflammatory cytokines pro- and anti-inflammatory. Cytokines such as IL-1, IL-2, and other mediators of inflammation observed in PE IL-8, TNF-α, and IFN-γ are proinflammatory, and in- [47] . Austgulen et al. [48] showed that levels of the soluble creased levels of such proinflammatory cytokines are as- adhesion molecules ICAM-1, VCAM-1, and E-selectin sociated with pregnancy complications such as preterm are increased in preeclamptic pregnancies, while levels of delivery [63] and intrauterine growth retardation [64] .
Cytokines in the Placenta
While PE is associated with increased levels of proin- flammatory cytokines, it is also associated with decreased Cytokines are produced by cells of normal placentas placental production of the anti-inflammatory cytokine and by leukocytes infiltrating the placenta, and receptors IL-10 [93–95] . Considering that IL-10 is a strong suppres-for cytokines are also expressed in the placenta; thus, both sor of proinflammatory cytokines such as IFN-γ and sources and targets of cytokines are present in the pla- TNF-α, it is suggested that the placenta responds to hy- centa [51, 65, 66] . Proinflammatory cytokines are pro- poxia in PE with insufficient IL-10 production, leading to duced by placental trophoblasts and also by macrophages increased or uncontrolled production of pro-inflammato- and stromal cells of the placenta [67–69] . The anti-in- ry cytokines [66] . Furthermore, IL-10 has anti-apoptotic flammatory cytokines IL-4 and IL-10 are also secreted by and anti-inflammatory capabilities, and it is therefore quite placental tissues [70] . Cytokines have been shown to play likely that the decreased IL-10 in the placenta is at least beneficial roles in several normal physiologic processes in partly responsible for the increased apoptosis of the tro- the placenta; these include trophoblast invasion and dif- phoblast seen in PE [96–98] . While apoptosis is actually ferentiation and placental proliferation and angiogenesis necessary for normal placentation, excessive apoptosis or [51, 71, 72] .
inadequate clearance of apoptotic debris may lead to in- Widespread upregulation of cytokines in preeclamp- creased production of proinflammatory cytokines by mac- tic placentas, including proinflammatory cytokines like rophages [99] . In addition to proinflammatory cytokines, TNF-α and their receptors, have been shown in DNA mi- decidua from a murine model of PE display higher levels croarray studies [73] . The expression and secretion of of GM-CSF as well as increased numbers of both macro-TNF-α [74–76] and IL-1 [77–79] are elevated in the pla- phages and dendritic cells when compared to control ani- centas of preeclamptic women. Hypoxia-reoxygenation mals [100] . Furthermore, TNF-α and IL-1 induce increased due to intermittent perfusion of the placenta has been production of GM-CSF by cultured decidual cells, leading shown to induce the production of TNF-α and IL-1 [75, to the suggestion of important roles for GM-CSF in induc-80–82] ; Benyo and colleagues [83, 84] demonstrated in- ing the activation of macrophages and dendritic cells in PE.
creased production of the proinflammatory cytokines TNF-α and IL-1 by the normal human placenta under con-ditions of low oxygen tension. Considering that placental Cytokines in the Periphery
hypoxia occurs in PE, this could well explain the elevated production of these two cytokines. High local production Levels of proinflammatory cytokines are increased in of TNF-α may have significant effects, including increased the blood and in blood leukocytes in PE. Elevated concen- trophoblastic apoptosis resulting in enhanced syncytial trations of TNF-α have been observed in the blood of shedding and impaired placental function [85] .
women with PE [101–105] . The placenta may not be the Elevated levels of other proinflammatory cytokines, major contributor to the high TNF-α levels seen in pe- i.e. IL-2 [78] and IL-18 [86] , have also been shown in pre- ripheral blood [84] , and in fact peripheral leukocytes, eclamptic placentas. IL-18 is a proinflammatory cytokine which are in any case in an activated state in PE [106] may which, in the presence of IL-12, tips the balance of im- contribute significantly to the TNF-α levels in peripheral mune reactivity towards a Th1 phenotype. High levels of blood [107] . Levels of soluble TNF-α receptor, a more re-IL-18 along with high levels of IL-12 [87] in PE are pro- liable marker for TNF activity, are also increased in PE as posed to cause Th1 dominance [88] . Lockwood et al. [89] compared to normal pregnancies [108] . Support for a demonstrated higher levels of IL-6 mRNA and protein in cause-and-effect association between TNF-α and PE leukocyte-free decidual cells from subjects with PE. Hu- comes from Sibai et al. [109] who showed that serum lev- man endometrial endothelial cells have been recently els of TNF-R2 receptor are indeed elevated prior to overt shown to be capable of phagocytosing apoptotic tropho- PE, suggesting a pathogenetic role for these proinflam- blasts and then secreting the proinflammatory cytokine matory cytokines.
IL-6 [90] ; this might be one of the mechanisms that con- Similarly, enhanced plasma levels of IL-1 [77] , IL-2 tribute to the inflammatory response seen in preeclamp- [110] , IL-6 [83, 101, 111, 112] , IL-8, and IL-18 [86] have tic placentas. Increased production of IFN-γ, a Th1 pro- been reported in preeclamptic women. Elevations of IL-6 inflammatory cytokine, has been found in decidual lym- and IL-8 have also been shown in the amniotic fluid of phocytes [91] and choriodecidual cells of placentas [92] preeclamptic patients [113] ; in fact, elevated levels of IL-6 from preeclamptic pregnancies.
have been shown to be associated with the onset of PE.
A recent study using a multiplex suspension array tribute to this in great part as these have been shown to technique compared levels of cytokines, chemokines, and stimulate the production of the proinflammatory cyto- adhesion molecules in normotensive pregnancies versus kines TNF-α, IL-12, IL-18, IL-1β, IL-6, and IL-8 by preeclamptic pregnancies . Serum from women monocytes [126] in PE. Cytokines may contribute to an with PE had increased Th1/Th2 cytokine ratios as well as increased release of trophoblast microparticles by stimu-increased levels of the cytokines IL-6 and TNF-α, the che- lating enhanced trophoblast apoptosis, and subsequently mokines IL-8, IP-10, and MCP-1, and the adhesion mol- these microparticles could cause elevated systemic pro- ecules ICAM-1 and VCAM-1, supporting the existence of duction of proinflammatory cytokines, thus supporting a systemic proinflammatory condition in PE.
the contention that cytokines play key roles in both stag- In contrast to the generally increased levels of proin- es of PE. In addition to Th1 and Th2 cells, T cells may flammatory cytokines, the blood levels of some anti-in- also differentiate into the distinct lineages of Treg and flammatory cytokines such as IL-4 [92, 115] and IL-10 Th17 cells. Treg cells play key roles in the regulation of [95] are reduced in patients with PE.
inflammation, while Th17 cells secrete the proinflamma- The production of cytokines by peripheral blood tory cytokine IL-17 and mediate potent tissue inflamma- mononuclear cells (PBMC) has been investigated in sev- tion. The numbers of a subset of regulatory T cells with eral studies. Maternal PBMC produce higher levels of the immunosuppressive capabilities, i.e. Treg cells, are sig- proinflammatory cytokines TNF-α [116] , IFN-γ [116– nificantly lower in PE compared to normal pregnancies 118] , IL-2 [104, 119] , IL-1 [120] , IL-6 [120] , and IL-8 [127] , while Th17 cells are increased [11] . The increase [105, 111, 120] . On the other hand, reduced production in proinflammatory Th17 cells and the decrease in the of IL-10 [111, 117, 118, 121] and IL-5 by PBMC from pa- immunosuppressive Treg cells is proposed to contribute tients with PE [111] has been reported.
to the pathophysiology of PE [128] via the induction of We conducted a study designed to ascertain whether a unbridled inflammation and endothelial dysfunction Th1-biased cytokine profile exists in women with PE as [11] . However, the laboratory of Zenclussen demonstrat-compared to normal pregnant women. We found that ed that the levels of Treg cells were similar in PE and nor-significantly higher levels of the proinflammatory cyto- mal pregnancy, questioning the role of Treg cells in kines IFN-γ and TNF-α were produced by women with averting PE [129] .
PE versus normal pregnant women, who on the contrary showed significantly greater production of the Th2 cyto-kines IL-4, IL-5, and IL-10. A comparison of the ratios of Mechanisms of Action of Cytokines in PE
Th2 to Th1 cytokines indicated significantly higher Th1/proinflammatory cytokine production in PE as compared The pathophysiologic mechanisms underlying the ini- to normal pregnancies [122] . Flow cytometric measure- tial placental changes and subsequent development of en- ment of intracellular cytokines demonstrated a shift to- dothelial dysfunction, hypertension, proteinuria, and wards predominantly Th1-type reactivity in PE [119] . edema in PE have been the subject of intense investiga- The increased levels of activated T cells [123] and the tilt tion over the years, and these aspects are now much better towards Th1 dominance in PE suggests important roles understood. PE is basically a condition of generalized en-for T cells in the pathogenesis of PE. There appears to be dothelial cell dysfunction [12, 23] ; the disturbed endothe-a clear increase in Th1 versus Th2 reactivity in women lium results in the well-known classical features of PE – with PE [42, 124] , and this has been shown to be initiated the hypertension is attributable to vasoconstriction, the before the clinical manifestation of PE, suggesting a cause- proteinuria is attributable to glomerular endotheliosis, and the edema is attributable to increased vascular per- Zenclussen [125] described a mouse model of PE in meability [47] .
which the adoptive transfer of Th1-like cells into preg- Generalized activation or injury of maternal vascular nant mice provokes PE symptoms such as increased BP endothelial cells leading to microthrombus formation and glomerulonephritis accompanied by proteinuria, in and vasospasm [130] is an important observation in PE. addition to effecting an inflammatory profile among Given the powerful effects of cytokines on endothelial uterine immune cells. This study provides strong support cells ( table 1 ), the increased tendency for maternal blood for a role for Th1-type reactivity in PE [125] .
cells to produce inflammatory cytokines in PE is signifi- What stimulates the production of proinflammatory cant. Maternal proinflammatory cytokines are likely to be cytokines in PE? Trophoblast microparticles may con- the most important effectors of these effects [42, 100, 101, Table 1. Inflammatory cytokines and endothelial dysfunction
increased activation of neutrophils [140] , while IL-6 is known to activate endothelial cells [89] , to induce in- creased permeability of endothelial cells, and to bring about systemic effects that resemble the inflammatory Increases the expression of adhesion moleculesIncreases vascular permeability It may be pertinent to refer to another factor that ap- pears to be involved in the pathogenesis of PE. Zenclussen Increases thrombin production and coagulationInduces the production of platelet-activating factor et al. [141] showed that the expression of the heme-de- Stimulates the expression of adhesion molecules grading enzymes heme oxygenases (HO)-1 and HO-2 is reduced in PE. They suggested that low expression of HO-2 may lead to enhanced levels of free heme at the feto-maternal interface, followed by upregulation of ad-hesion molecules which would then encourage the migra-tion of inflammatory cells to the feto-maternal interface; this points to the involvement of HO in PE [142] . HO-1 107, 109, 113, 122] . In fact, Redman et al. [131] affirmed plays an important role in placental vasculature develop- that the clinical features of PE are best described as an ex- ment, and a deficiency in HO-1 may contribute to preg- cessive maternal inflammatory response mediated by cy- nancy complications, such as PE. The unique combina- tokines, and that cytokine action is one of the most attrac- tion of tissue-protective, smooth-muscle-relaxing, and tive hypotheses of immunological dysfunction in this angiogenesis-regulatory properties makes HO-1 a key syndrome.
player in the maintenance of a healthy pregnancy through At the level of the placenta, the cytokines IL-6 and a direct effect on placental structural and vascular devel- TNF-α were shown to induce excessive or abnormal opment [143] .
apoptotic and necrotic death of trophoblast cells; these A fascinating nexus between cytokines and BP control cells were shown to induce endothelial activation when is now being unraveled. Hayashi et al. [144] reported a shed [132] . Thus cytokines appear to be involved in the positive correlation between increased production of the early (i.e. stage 1) events of PE. The pattern of increased inflammatory cytokines IL-2, IFN-γ, and TNF-α by pe-placental and systemic cytokines appears to be consistent ripheral blood leukocytes in PE and mean BP. Chronic with increased systemic inflammatory activation, the re- infusions of IL-6 or TNF-α into normal pregnant rats in- lease of vasoconstrictory factors, endothelial dysfunction, crease arterial pressure and affect renal hemodynamics and hypertension, which are all part of the syndrome of [41] . A recent study on pregnant baboons showed that the PE [133] . The widespread maternal vascular endothelial infusion of TNF-α is followed by an increase in systolic dysfunction is suggested to be caused by proinflamma- and diastolic BP and proteinuria, indicating that TNF-α tory cytokines [66] and, along with other mediators such can induce the clinical and biochemical features of hu-as endothelin and thromboxane, are proposed to contrib- man PE and also showing a clear association of TNF-α ute to hypertension, proteinuria, and edema [130] . Benyo with endothelial dysfunction and BP control et al. [83] pointed out that proinflammatory cytokines are TNF-α activates the endothelin system in placental, vas- ‘notorious’ for effecting changes in the endothelium in cular, and renal tissues, while IL-6 activates the renin-the same manner as that seen in PE. TNF-α has potent angiotensin system [41] . Proinflammatory cytokines pro-effects on endothelial and platelet function, it enhances duced in PE may contribute to hypertension by inducing coagulation, microvascular leakage, activation of vaso- the production of vascular mediators that result in vaso- constrictive endothelial cells, and production of antian- constriction and consequently hypertension [146] . Cyto- giogenesis factors like tissue factor [134, 135] . TNF-α and kines are suggested to be linked to hypertension by pro- IL-1 cause increased production of thrombin, platelet-ac- voking inflammation, which would result in vascular in- tivating factor, and vascular cell adhesion molecule-1, in- jury and may also contribute to elevated BP by causing creased endothelial cell permeability [136] , and enhanced kidney injury [147] . In a rat model of PE, Tinsley et al. coagulation, and thus instigate inflammatory responses [148] showed that the Th1-like cytokines IL-2, IL-12, and [137–139] . TNF-α has been shown to induce the activa- IFN-γ were elevated; immunosuppression with azathio- tion of endothelial cells and to cause endothelial damage prine or mycophenolate not only resulted in a significant [75] . Increased concentrations of IL-8 are associated with reduction of Th1 cytokines but also decreased the associ- ated hypertension, proteinuria, and endothelial dysfunc- Table 2. Cytokines and hypertension
Increased Th1 reactivity [42, 122] and Th17 levels Infusion of TNF-α or IL-6 into pregnant rats increases arterial BP.
[149] in PE may induce exaggerated systemic inflamma- Infusion of TNF-α into pregnant baboons causes increases in BP tion and vascular endothelial dysfunction. That TNF-α and proteinuria.
may contribute directly to proteinuria is supported by a TNF-α activates the endothelin system in the kidneys.
recent study on diabetic nephropathy in which a positive IL-6 activates the renin-angiotensin system.
correlation was observed between plasma TNF-α levels and urinary protein concentrations [150] .
Proinflammatory cytokines cause vasoconstriction.
Suppression of proinflammatory cytokines results in reduction of hypertension and proteinuria.
Immunomodulation for Therapeutic Intervention in
There is a negative correlation between IL-10 levels and BP.
Infusion of IL-10 leads to improvement of PE-like symptoms in mice.
The possibility of rational development of immuno- modulatory approaches for the treatment of PE is sup-ported by research on anti-inflammatory cytokines like IL-10 and on the suppression of proinflammatory cyto-kines.
considered for PE. This study and the experiments on in- A negative correlation has been reported between BP fusion of IL-10 offer a scope for optimism that better un- and serum levels of IL-10 [94] , and this has also been derstanding of the pathogenesis of this rather mysterious demonstrated experimentally in nonhuman primates disorder will lead to the rational development of treat- [151] . A recent elegant study by Chatterjee et al. [152] ments. Our work demonstrating the effects of the orally showed that TLR3 activation during murine pregnancy administered progesterone derivative dydrogesterone induced an increase in systolic BP and endothelial func- (6-dehydro-9β, 10α-progesterone) is pertinent. Dydro- tion, demonstrating a connection between immune acti- gesterone (Duphaston ® ) is a potent orally administered vation and symptoms of PE. TLR3 activation was shown progestogen, similar to endogenous progesterone in its to be associated with a proinflammatory state along with molecular structure and pharmacological effects, with a an increase in proinflammatory cytokines. Interestingly, high affinity for the progesterone receptor. We have a deficiency in IL-10 along with TLR3 activation brings shown that dydrogesterone brings about a significantly about an exacerbation of PE symptoms; the addition of reduced secretion of the Th1 cytokines IFN-γ and TNF-α recombinant IL-10 prevented these symptoms, demon- and a significant increase in the levels of the Th2 cyto- strating the importance of IL-10 in this equation. These kines IL-4 and IL-6 [155, 156] . In view of the fact that the observations are significant given the well-documented relative levels of Th1 and Th2 cytokines are probably of anti-inflammatory properties of IL-10 and the demon- greater importance than their absolute levels alone, we stration that IL-10 deficiency is associated with PE-like calculated the ratios of Th1 to Th2 cytokines and found a symptoms. In pregnant baboons, the administration of marked reduction in the Th1/Th2 ratios (e.g. IFN-γ/IL-4, anti-IL-10 antibody results in a significant increase in IFN-γ/IL-10) in PBMC cultures containing dydrogester-mean arterial pressure via regulation of vasodilation one. Thus, dydrogesterone redirects Th1/Th2 profiles in [151] . Chatterjee et al. [152] proposed that recombinant lymphocytes from women with recurrent miscarriage IL-10 may be considered for use in preventing PE. More [155] and preterm delivery [156] by downregulating the evidence of the important role of IL-10 comes from ob- production of proinflammatory cytokines and upregulat- servations that IL-10 knockout mice have mild hyperten- ing the production of anti-inflammatory cytokines [157] . sion, endothelial dysfunction, and inflammation [153] .
This could well result in a substantial swing in Th1/Th2 The possibility of manipulating cytokine production reactivity towards the pregnancy-conducive Th2 profile for therapeutic intervention in PE is supported by the re- and away from the potentially harmful Th1 profile. In cent study of Keiser et al. [154] . This study on pregnant fact, dydrogesterone downregulates the very cytokines, rats showed that progesterone inhibits TNF-α-stimulated i.e. TNF-α and IFN-γ, that are implicated in many of the production of endothelin-1 by endothelial cells and sug- manifestations of PE. Redman et al. [131] suggested that gested that such immunomodulatory approaches may be the clinical features of PE are best described as an exces- sive maternal inflammatory response, mediated by cyto- eventually lead to ‘systemic, diffuse endothelial cell dys- kines. If indeed a Th1 predominance is responsible for PE function’, the fundamental pathophysiological feature of and if Th2 bias is associated with a successful pregnancy, this syndrome.
then immunomodulatory agents like dydrogesterone While understanding the etiology and pathophysiol- may be worth considering for use in PE. It is tempting to ogy of PE is certainly of interest from a basic medical sci-speculate that modulation of cytokine profiles by thera- ence perspective, it also has important implications for peutic supplementation with progestogens like dydroges- the treatment and management of this dangerous com- terone may be an attractive treatment option for PE.
plication. There is renewed optimism that basic and clin-ical research which has helped elucidate the pathogenesis of this disease will lead to the rational design of interven- Conclusion
tions for the management and treatment of this impor-tant and common complication of pregnancy.
Sufficient evidence from animal and human studies has now been gathered to reveal the pathogenesis of PE on the basis of the influence of cytokines both in the pla- Acknowledgements
centa and in the periphery. A unifying hypothesis for PE is that inadequate trophoblast invasion and remodeling This work was supported by Kuwait University Research Ad- of spiral arteries stimulate placental ischemia and hypox-ia via intermittent perfusion of the placenta; this results in an increased release of trophoblast microparticles into Disclosure Statement
the maternal circulation followed by increased produc-tion of maternal proinflammatory cytokines and activa- The author declares no conflict of interest. tion of maternal endothelial cells. This is proposed to References
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