http://informahealthcare.com/jmfISSN: 1476-7058 (print), 1476-4954 (electronic)

J Matern Fetal Neonatal Med, 2014; 27(15): 1513–1517! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2013.861415

ORIGINAL ARTICLE

Plasma IL-17, IL-35, interferon-g, SOCS3 and TGF-b levels in pregnantwomen with preeclampsia, and their relation with severity of disease

Zehra Sema Ozkan1, Mehmet Simsek1, Fulya Ilhan2, Derya Deveci3, Ahmet Godekmerdan2, and Ekrem Sapmaz1

1Department of Obstetrics and Gynecology, 2Department of Immunology, Firat University School of Medicine, Elazig, Turkey, and 3School of Health

Services, Firat University, Elazig, Turkey

Abstract

Objective: To research the hypothesis of preeclampsia (PE) is associated with increased systemicinflammatory responses of Th1-type as well as decreased Th2-type responses; we evaluatedthe maternal plasma levels of IFN-gamma, TNF-alpha, TGF-beta, IL-4, IL-6, IL-10, IL-17, IL-35 andSOCS3 in preeclamptic and healthy pregnants.Methods: This study was conducted with 40 preeclamptic (study group) and 40 normotensivepregnant (control) women in third trimester when they were admitted to the labor and deliveryunit. The extracted maternal plasma samples were assayed by an enzyme-linked immuno-sorbent assay. Statistical analysis was performed by SPSS 16.0 version.Results: While IFN-gamma and TGF-beta levels of preeclamptic women were significantly higher(p50.01), IL-35 and IL-17 levels of preeclamptic women were significantly lower (p50.01)than those of controls. The ratios of IFN-gamma/IL-10, IFN-gamma/IL-6, IFN-gamma/IL-4 weresignificantly high and ratio of IL-35/IL-17 was significantly low in the PE group compared tothose in the control group. Maternal plasma SOCS3 levels showed negative correlation withblood pressure and proteinuria severity, but none of the cytokines showed influence on bloodpressure and proteinuria after adjusting for maternal and gestational age.Conclusions: Increased IFN-gamma/TGF-beta production and reduced IL-35/IL-17/SOCS3production in preeclamptic women may lead to less cytokine inhibitory activity in PE, whichmay account for the increased proteinuria and blood pressure in PE.

Keywords

IL-17, IL-35, inflammation, preeclampsia,SOCS3

History

Received 23 July 2013Revised 29 October 2013Accepted 29 October 2013Published online 29 November 2013

Introduction

Preeclampsia (PE) is still a leading cause of maternal and

fetal morbidity and mortality. Despite decades of intense

research on the problem, there is no early predictive test to

recognize those at risk. Recently, altered immune responses

have been suspected to be involved in PE pathogenesis [1].

During pregnancy, the balance of T helper1 (Th1) (cell-

mediated immunity) and Th2 (humoral immunity) cytokines

is characterized by an initial prevalence of Th2 cytokines,

followed by a progressive shift toward Th1 predominance

late in gestation. Interleukin-2 (IL-2), interferon-gamma

(IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha)

are the cytokines of Th1; IL-4, IL-5, IL-6, IL-10 are the

cytokines of Th2. The abnormality in Th1/Th2 balance

may initiate and intensify the cascade of inflammatory

cytokine production involved in adverse pregnancy outcomes

as spontaneous abortion, intrauterine growth restriction, PE

and preterm delivery [2–4]. Besides the imbalance of Th1 and

Th2 cells, alterations of the prevalence of Th17 and regula-

tory T (Treg) cells have also been suggested to contribute to

pathogenesis of PE [5–11]. And also normal cellular

responses to cytokines via activators (Signal Transducers

and Activators of Transcription- STATs) or supressors

(Suppressor of cytokine signalling- SOCS) is one of the

investigation topic about immune balance in pregnancy

[12,13].

In this study, we researched the hypothesis that PE is

associated with increased systemic inflammatory responses

of Th1-type as well as decreased Th2-type responses

compared with normal pregnancy; and for this hypothesis

we evaluated the maternal plasma levels of IFN-gamma,

TNF-alpha, TGF-beta, IL-4, IL-6, IL-10, IL-17, IL-35 and

SOCS3 in preeclamptic and healthy pregnants.

Materials and methods

This study was conducted with 40 preeclamptic (study group)

and 40 normotensive pregnant (control) women in third

trimester at Firat University Hospital, Department of

Obstetrics and Gynecology, after local ethical committee

approval between August 2011 and August 2012.

Normal pregnant women were recruited when they were

admitted to the labor and delivery unit. Normal pregnancy

was defined as pregnancy with normal blood pressure (5140/

90 mmHg), no proteinuria, and absence of obstetric and

Address for correspondence: Zehra Sema Ozkan, IVF Unit, FiratUniversity Hospital, 23119, Elazig, Turkey. Mobile: +905053983219.E-mail: zehrasema@yahoo.com

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medical complications. Women diagnosed with PE were

recruited when they were admitted to the labor and delivery

unit. Diagnosis of PE was defined as follows: sustained

systolic blood pressure of4140 mmHg or a sustained diastolic

blood pressure of 490 mmHg on two separate readings;

proteinuria measurement of 1þ or more on dipstick, or 24-h

urine protein collection with 4300 mg in the specimen.

Proteinuria severity was defined according to the grading

of dipstick. Smokers and patients with signs of infection

were excluded. To avoid clinical phenotypic differences in

preeclamptic patients, patients complicated with HELLP

syndrome (hemolysis, elevated liver enzyme and low platelet

count), diabetes, and/or renal disease were excluded. Signed

consent was obtained at the time of enrollment.

Maternal prepartum venous blood samples were drawn

using a polypropylene syringe and a butterfly needle and then

7 ml blood was transferred to tubes. The samples were

centrifuged at 2500 rpm at 4� C for 15 min, and stored at

�20 �C until analysis. The extracted plasma samples were

assayed by an enzyme-linked immunosorbent assay (ELISA)

using commercially available kits for IL-17, IFN-g, TNF-a,

TGF-b, IL-6, IL-4, IL-10 (Boster Biological Technology,

Fremont, CA) and SOCS3 and IL-35 (USCN, Wuhan, China)

according to the manufacturer’s instructions. The samples

were analyzed by the same staff in the same laboratory

conditions. Within and between assay variations were less

than 6% and 8% for all ELISA assays, respectively.

Statistical analysis was performed by Statistical Package

for Social Sciences 16.0 (SPSS Inc., Chicago, IL) version.

Results were presented as mean�SE. Differences in con-

tinuous variables were analyzed by Student’s t-test or Mann–

Whitney U-test according to distribution of data. Differences

between groups for categorical variables were analyzed using

the chi-square test or Fisher’s exact test, as appropriate.

The relation between plasma cytokine levels and clinical

characteristics was evaluated by the Spearman correlation

test. Logistic regression analysis was employed to identify the

cytokines which could have influenced on blood pressure,

proteinuria, birthweight and Apgar1 score. p Values of50.05

were considered as statistically significant.

Results

Demographic and clinical characteristics of all women in

the study were presented in Table 1. Gestational week,

birth-weight and Apgar1 score of preeclamptic women were

lower than of controls. Levels of liver transaminases of

preeclamptic women were higher than that of normotensive

pregnants. MgSO4 treatment was applied to 67.6% of

preeclamptic women.

Cytokine levels of all women in the study are presented in

Table 2. IL-4, IL-6 and IL-10 plasma levels of preeclamptic

women were higher and SOCS3 and TNF-alpha plasma levels

of preeclamptic were lower than those of the control group,

but the differences were not significant. In preeclamptic

women; IFN-gamma and TGF-beta levels were significantly

higher (p50.01) and IL-35 and IL-17 levels were signifi-

cantly lower (p50.01) than those of controls. The comparison

of Th1 and Th2 cytokine ratios in two groups revealed out the

following findings: IFN-gamma/IL-10, IFN-gamma/IL-6 and

IFN-gamma/IL-4 ratios of the PE group were significantly

higher than those of the control group (p50.01). IL-35/IL17

ratio was significantly low in the PE group compared to that

in the control group (p50.01). There was no significant

difference between groups for the ratios of TNF-alpha/IL-10,

TNF-alpha/IL-6 and TNF-alpha/IL-4.

In correlation analysis; we observed the following rela-

tions. (1) The severity of proteinuria showed negative

correlation with maternal plasma SOCS3 levels (R¼ 0.41,

p¼ 0.01). (2) Maternal plasma SOCS3 levels showed positive

correlation with gestational age (R¼ 0.24, p¼ 0.04). (3) The

severity of proteinuria showed positive correlation with

maternal plasma IFN-gamma levels (R¼ 0.3, p50.01).

(4) Liver transaminases showed positive correlation with

maternal plasma IL-10 levels (R¼ 0.23, p¼ 0.04 for ALT and

R¼ 0.26, p¼ 0.02 for ALT). (5) IL-6 levels showed negative

correlation with TNF-alpha levels (R¼ 0.22, p¼ 0.04).

(6) The correlation between blood pressure and cytokines

are presented in Table 3. While IFN-gamma and TGF-beta

showed positive correlation with blood pressure; IL-17, IL-35

Table 1. Demographic and clinical characteristics of all women in thestudy.

ParametersPreeclampsia

(n¼ 40)Control(n¼ 40) p value

Age (years) 31.1� 1 32.1� 0.8 0.44Gestational week 35 (24–40) 38 (34–40) 50.01*Hemoglobin (g/dL) 12.2 (7–16) 11.6 (8.1–14.4) 0.15*Platelet� 1000(/mm3) 238� 15 263� 15 0.24ALT (IU/L) 18.5 (8–40) 17 (6–32) 0.03*AST (IU/L) 30 (16–45) 23 (11–38) 0.01*Birth weight (g) 2007 (510–3900) 3170 (2014–3900) 50.01*Apgar1 score 8 (4–9) 9 (5–10) 0.04*

Values are presented as mean� SE and median (min–max);ALT¼alanine aminotransferase; AST¼ aspartate aminotransferase.

*Mann–Whitney U-test.Bold values statistically significant differences.

Table 2. Plasma cytokine levels of all women in the study.

CytokinesPreeclampsia

(n¼ 40)Control(n¼ 40) p value

IL-17 (pg/mL) 1.28 (1.08–4.24) 1.5 (1–3.57) 0.44*IL-6 (pg/mL) 0.31 (0.01–8.2) 0.34 (0.01–6) 0.29*IL-4 (pg/mL) 1.24 (0.03–30.97) 1.5 (0–11) 0.75*IL-10 (pg/mL) 9.81 (8.58–10.04) 9.65 (6.15–10.04) 0.21*IL-35 (pg/mL) 6.65 (3.7–1000) 15.3 (3.5–987) 50.01*SOCS3 (pg/mL) 63.09 (4.2–703) 82.05 (5–714) 0.08*IFN-gama (pg/mL) 0.42 (0–27.3) 0 (0–5.86) 50.01*TGF-b (pg/mL) 2.6 (1.4–7.6) 1.9 (0.4–15.2) 50.01*TNF-a (pg/mL) 0.65 (0.3–10.3) 0.8 (0.09–62.2) 0.17*

Values are presented as median (min–max).*Mann–Whitney U-test.Bold values statistically significant differences.

Table 3. Correlation analysis between bloodpressure and cytokines.

Cytokine R value p value

IL-17 �0.34 50.01IL-35 �0.24 0.03IFN-gamma 0.36 50.01TGF-beta 0.23 0.03SOCS3 �0.27 0.01

1514 Z. S. Ozkan et al. J Matern Fetal Neonatal Med, 2014; 27(15): 1513–1517

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and SOCS3 showed negative correlation with blood pressure.

(7) SOCS3 showed positive correlation with Apgar1 score

(R¼ 0.23, p¼ 0.04) and IL-17 showed positive correlation

with birth-weight (R¼ 0.25, p50.01).

In regression analysis; after adjusting for gestational age

and maternal age; only IL-4 (AOR¼ 0.8, 95% CI¼ 0.70–

0.99, p¼ 0.048) and TGF-beta (AOR¼ 0.7, 95% CI¼ 0.58–

0.98, p¼ 0.039) were the covariates those had influence

on proteinuria severity but, SOCS3 (AOR¼ 1, 95%

CI¼ 0.996–1.004, p¼ 0.7) and IFN-gamma (AOR¼ 0.5,

95% CI¼ 0.25–1.05, p¼ 0.06), showed no influence on

proteinuria severity. After adjusting for gestational age,

maternal age and proteinuria; IL-4 (AOR¼ 0.9, 95%

CI¼ 0.79–1.11, p¼ 0.4) and TGF-beta (AOR¼ 1.04, 95%

CI¼ 0.72–1.5, p¼ 0.8) showed no influence on blood pres-

sure. After adjusting for maternal age, gestational age and

blood pressure; none of the cytokines showed influence

on proteinuria severity. After adjusting for maternal age,

gestational age, proteinuria and blood pressure; none of

the cytokines showed influence on birthweight and Apgar1

score.

Discussion

In this study, decreased maternal plasma IL-35 levels in PE

and its negative relation with blood pressure were firstly

investigated in our knowledge. We demonstrated that:

(1) maternal plasma SOCS3 levels showed positive correl-

ation with gestational age and showed negative correlation

with proteinuria severity, but this relation disappared after

adjusting for maternal age and gestational age; (2) while

maternal plasma IL-17 and SOCS3 levels have negative

impact on blood pressure, maternal plasma IFN-gamma and

TGF-beta levels showed positive correlation with blood

pressure, but these relations disappeared after adjusting for

maternal age, gestational age and proteinuria; (3) the ratios of

IFN-gamma/IL-10, IFN-gamma/IL-6, IFN-gamma/IL-4 were

significantly high and ratio of IL-35/IL-17 was significantly

low in the PE group compared to those in the control group.

The limitations in our study were as follows: firstly, our

control group were not consisted of gestational age-matched

healthy pregnants. Secondly, we did not know the placental

levels of cytokines.

The mechanism for increased inflammatory response in PE

is largely unknown. IL-6 is an intriguing cytokine and studies

have shown that IL-6 acts as both a proinflammatory and an

anti-inflammatory cytokine. High maternal plasma IL-6 and

TNF-alpha levels in PE was reported [10,14–16]. Pinheiro

et al. studied maternal plasma TNF-alpha, IFN-gamma, IL-4,

IL-5, IL-10, IL-1b, IL-6, IL-8 and IL-12 levels of

preeclamptic women. They reported association between

severe preeclamptic state and high IL-6, IL-8 and IFN-gamma

levels, in other words proinflammatory cytokine dominancy

in PE [10]. Increased intracellular expression of IL-4, IL-10,

IL-13, IL-12, IFN-gamma and TNF was reported for

peripheric mononuclear cells of severe preeclamptic women

[17]. Molvarec et al. reported a bias toward pro-inflammatory

status in PE according to significant difference between

serum levels of preeclamptic and normotensive pregnants

for parameters of IL-2, IL-4, IL-6, IL-8 and IL-10 [18].

The evaluation of 31 preeclamptic and 67 normotensive

maternal plasma samples for the parameters of IL-2, IL-4,

IL-8, IL-10 and IFN-gamma revealed out no difference; but

an association between PE and increased TNF-alpha and IL-6

levels were noticed [19]. Tarnovska reported high serum

TNF-alpha, IFN-gamma and IL-2 levels in 34 preeclamptic

women compared to 16 healthy pregnant women [20]. Boji

et al. compared 32 biomarkers reflecting coagulation,

inflammation and angiogenesis between 114 preeclamptic

women and 100 healthy gestational and maternal age-matched

pregnant controls. Maternal plasma levels of IFN-gamma,

IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 and TNF were measured as

inflammation markers. They observed that IL-4 levels were

significantly low in preeclamptic women compared to that in

healthy pregnants under 32 gestational weeks. This difference

was not observed between groups over 32 gestational weeks

[21]. In our study; IL-4, IL-6 and IL-10 levels were high and

TNF-alpha levels were low in PE, but the differences were not

significant. IFN-gamma levels were significantly high in PE.

And IFN-gamma showed positive correlation with blood

pressure and proteinuria severity. Increased IFN-gamma/

IL-10, IFN-gamma/IL-6, IFN-gamma/IL-4 ratios in our

population pointed out the impaired Th1/Th2 balance in PE.

Sudanese women with PE showed high IL-10 levels, but

Iranian women with PE did not [22,23]. The varied results

among the studies may arise from the difference of sample

sizes and ethnicity. Interestingly, in a recent study, it was

reported that in preeclamptic pregnancies the placentas of

male fetuses were associated with significantly higher

expression of inflammatory molecules (TNF-alpha, IL-6

and IL-8) compared to placentas of female fetuses [24].

Wang et al. observed phenotypic and functional differen-

tiation of dendritic cells with production of IFN-gamma and

IL-17 when cultured with different cytokines in PE [11].

Dhillion et al. observed increament of blood pressure after

IL-17 infusion on pregnant rats [25]. But in our study we

observed inverse relation between blood pressure and IL-17

levels. In an another study, it was noticed that the percentage

of T lymphocytes producing IL-17 was significantly higher in

PE than in healthy, normotensive pregnant women in the third

trimester [6]. Th17 cells seem to participate in successful

pregnancy processes and recent data show the reciprocal

development of pathways between Th1/Th17 may play a

major role in PE [26]. Toldi et al. demonstrated increased

IL-17 expression in PE [5]. Martınez-Garcıa et al. noticed a

gradual elevation on plasma IL-17 levels from first trimester

to third trimester in healthy pregnants [27]. The differenti-

ation of both Th17 and Treg cells requires TGF-beta [28].

The investigators have suggested that higher levels of soluble

endoglin, an inhibitor of TGF-beta receptor signaling, in

preeclamptic women may bias toward IL-17 production [29].

But in our study, IL-17 levels were significantly low despite

significantly high TGF-beta levels in PE. This result may

arise from the lower gestational age of preeclamptic women

than of healthy pregnants. In this study, TGF-beta levels

showed positive correlation with blood pressure. Another

researchers investigated serum TGF-beta1 levels and TGF-

beta1 gene promotor region -800G!A and -509C!T

polymorphisms in 142 preeclamptic and 140 normal pregnant

Iranian women. They observed significantly high serum

DOI: 10.3109/14767058.2013.861415 Preeclampsia and IL-35 1515

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TGF-beta1 levels in preeclamptic women, but there was no

difference between PE and control groups for TGF-beta1 gene

polymorphisms [30].

A novel inhibitory cytokine, IL-35 is produced by

Foxp3(þ) regulatory T cells (Tregs) and mediates maximal

suppression of Tregs. First-trimester human trophoblast cells

expressed and secreted IL-35, which might contribute to

suppressive capacity of maternal immune cells. IL-35 may be

an important factor of the cytokine network regulating local

immune responses during human pregnancy [31]. IL-35 is

also an anti-inflammatory cytokine suppressing the immune

response through the expansion of Tregs and suppression of

Th17 cell development [32,33]. It was thought that IL-35

would be promising to cure autoimmune and inflammatory

diseases [34]. We have not noticed a study about IL-35 levels

in PE. Our study is the first on this topic. We observed

significantly low IL-35 levels in PE and this condition may

refer to inflammatory status in PE. Interestingly despite low

IL-35 levels, IL-17 levels were also low in our preeclamptic

population. But both of these cytokines showed negative

correlation with blood pressure.

A few study recently investigated SOCS3 in PE and the

researchers reported decreased expression of SOCS3 in PE

[16,35]. IL-6 mediates anti-inflammatory response via induc-

tion of SOCS3 [16]. Enhanced SOCS3 gene expression

could promote IL-10 production by placental trophoblast

cells, suggesting that SOCS3 may play an important role in

regulation of cytokine-induced anti-inflammatory response

during pregnancy [36]. In our study, we observed low SOCS3

levels in PE and an inverse relation between plasma SOCS3

levels and proteinuria severity and blood pressure. Our low

SOCS3 levels in preeclamptic women may arise from low

gestational age of preeclamptic women.

Our results indicate an imbalance between inflammatory

and anti-inflammatory cytokines in PE. We concluded that

increased IFN-gamma/TGF-beta production and reduced

IL-35/IL-17/SOCS3 production in preeclamptic women

may lead to less cytokine inhibitory activity in PE, which

may account for the increased proteinuria and blood pres-

sure in PE.

Acknowledgements

We thank Dr Banu Kumbak, Prof. Dr Ali Risvanli, Gokcen

Ozdemir and staffs of our Obstetrics Department for their

help during the study.

Declaration of interest

This study was funded by Firat University Scientific Research

Foundation. All the authors declare that they have no conflict

of interest.

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DOI: 10.3109/14767058.2013.861415 Preeclampsia and IL-35 1517

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