Role of Some Cytokines on Reproduction

Middle East Fertility Society Journal (2011) 16, 220–223

Middle East Fertility Society Middle East Fertility Society Journal

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ORIGINAL ARTICLE Role of some cytokines on reproduction

Batool Mutar Mahdi *

Department of Microbiology, Al-Kindy College of Medicine, Baghdad University, AL-Nahda Square, Baghdad, Iraq

Received 11 December 2010; accepted 13 March 2011 Available online 9 April 2011

KEYWORDS Abstract Background: The etiology of female reproductive failure may be very complex owing to Infertility; a neuro-endocrine-immune association. Dysregulated immunity has been implicated in reproductive Cytokines; failure. Lower TH1 cytokines is supportive for physiological pregnancy. IL-10; Aim of the study: To measure serum levels of pro-inflammatory cytokines (tumor necrosis factor IL-6; (TNF-a), interferon-gamma (IFN-c) and anti-inflammatory cytokines (IL-10 and IL-6) in repro- IFN-c; ductive failure women. TNF-a Patients and methods: A cross- sectional study was carried out in Kammal El-Sammrari Hospital from 2008 to 2010. Forty-five women with reproductive failure participated in the study. Serum levels of cytokines (IL-6, IL-10, TNF-alpha and IFN-gamma) were done by Enzyme Linked Immuno Sorbent Assay (ELISA) and compared with age, body mass index and ethnicity matched thirty fertile women. Results: There is a significant increase in IL-10 (18.09) (p = 0.002) and IFN-c (49.62) (p = 0.0001) in women with reproductive failure. TNF-a and IL-6 showed no significance different with fertile group. Conclusions: There is increase in IL-10 and IFN-c in women with reproductive failure. 2011 Middle East Fertility Society. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction

Some of reproductive failure may be immunologically deter- mined. The genetic predisposition for cytokine production * Mobile: +964 1 077 02 553215. and its inﬂuence on infertility is directed by the genetic system E-mail address: [email protected] (1). Many cytokines are crucially important for reproductive processes and their role has been investigated in reproduction. 1110-5690 2011 Middle East Fertility Society. Production and Cytokines are immunoregulatory molecules responsible for hosting by Elsevier B.V. All rights reserved. determining the nature of immune response. It has been Peer review under responsibility of Middle East Fertility Society. suggested that lower index of TH1/TH2 immune response is doi:10.1016/j.mefs.2011.03.002 supportive for physiological pregnancy (2,3). IL-1 and IL-18 had an important factor in embryonic- endometrial dialogue, subsequent invasion, neoangiogenesis Production and hosting by Elsevier and embryo implantation, which is an essential step in mam- malian pregnancy (4). Other cytokines like IL-1-beta, IL-6 and Role of some cytokines on reproduction 221

TNF-alpha are essential in ovarian cycle regulation and play 3. Results an important function during growth and development of ovarian follicle (5). In addition to that, increased production There is no significant difference between mean age of infertile of Th1 cytokines such as TNF-alpha plus IFN-gamma com- women group which was 32.2 ± 6.1SD (ranging from 20 to 40 pared to the Th2 cytokine IL-10 is linked to infertility and years) and mean age of control group was 30.4 ± 9.1 SD recurrent spontaneous abortion (RSA) (6). Produced by Th1 (ranging from 19 to 39 years), also there was no significant dif- cells, cytokine Tumor necrosis factor alpha (TNF-alpha) is a ference in body mass index as demonstrated in Table 1. multifunctional proinflammatory cytokine secreted predomi- Cytokines profile showed significant increase in IL-10 nantly by monocytes/macrophages that has effects on lipid (18.09) (0.002) and IFN-c (49.62) (0.0001) in infertile women metabolism, coagulation, insulin resistance, and endothelial when compared with control group. In addition to that, there function and evidence was supported by previous studies in is no significant difference in IL-6 and TNF-a between two which higher serum levels of TNF-alpha were detected in groups as shown in Table 2. RSA groups and reproductive failure (7). It is suggested that Th1 cytokines trigger thrombotic/inflammatory processes at 4. Discussion the maternal uteroplacental blood vessels by activation of vas- cular endothelial cell procoagulant and administration of TNF-alpha to normal pregnant mice with significantly in- Immune response in normal pregnancy is more TH2-like, which creased fetal resorption (8). protects the fetus from being rejected (12). Th1 secrets proin- Therefore, anti TNF-alpha drugs may offer a new safe and flammatory cytokines (IFN-gamma and TNF-alpha) and Th2 effective approach to treating patients with Th1 cytokine secretes (IL-6, IL-8 and IL-10) (13). This study showed signifi- dependent infertility (9). In case of IFN-c, it is not essential cant increase in gamma IFN (49.62) (p = 0.000) in infertile for fetal survival in mice ablated for IFN-c giving to normal women when compared with fertile group. This was in agree- progeny (10). Significantly, higher serum levels of Th2 cyto- ment with Raghupathy planned, in 1997 (14) that Th1 cytokines kines, IL-6 and IL-10 were detected in normal pregnancy especially IFN-gamma are incompatible with successful (11). Thus, cytokines production is important to mount a type pregnancy. The other study found that IFN-c is not essential of immune response for pregnancy maintenance. for fetal survival because mice ablated for either IFN-c or We aimed to study T-helper 1 (Th1) (TNF- alpha and IFN- IFN-c receptor are viable and give offspring as homozygous gamma) and Th2 (IL-6 and IL-10) cytokines in peripheral young mating pairs (15). The other study found that IFN-c at blood of women with reproductive failure. implantation sites is harmful to or incompatible with gesta- tional success (16). IFN-c derived from uterine NK cells at 2. Patients and methods murine implantation sites at concentrations (under 10 U/mouse implantation site) is essential for normalcy of pregnancy and maintenance of decidual cell viability, remodeled maternal The study included 45 infertile women consulting Kammal El- arterial walls and inhibits excessive trophoblast growth and Sammrari Hospital from 2008 to 2010. The inclusion criteria invasion (17). So there is a challenge between Th1 and Th2 are patients suffering from infertility for one year whether pri- model (18,19). IFN-gamma is important for fetal survival and mary or secondary. Patients with other causes of infertility increased numbers of circulating IFN-c secreting cells in normal (ovarian, tubal, galactorrhea, hormonal, infection) were ex- pregnancy (20). This discrepancy with our result may be due to cluded from the study. In addition to that, females with auto- type of patients’ selection, body mass index, ethnicity and small antibodies, autoimmune diseases, antisperm antibodies, number of patients studied. antiphospholipid antibodies, other immune problems and fe- The other cytokine was TNF-alpha, our results showed no males who their couples are infertile were excluded from the significant difference with control group. Yui et al. (21) and study. Thirty normally ovulating women matched for age Todt et al. (22) assumed that TNF-a suppressed the growth and body mass index (BMI) served as control group. Both of trophoblasts by inducing apoptotic changes in these cells. groups are of same ethnicity. This normalcy of TNF-alpha in our study may be due to pres- The permission of medical ethics committee was obtained ence of HLA-G expressing cells adjusting the capability of for both groups (infertile and fertile). The Ethical Committee peripheral blood mononuclear cells to release cytokines of Al-Kindi College of Medicine, Baghdad University and (23). TNF-alpha had anti reproductive effects (24) exerting Al-Kindi Teaching Hospital approved the study and all sam- an autocrine activation (25) and anti embryo effects triggering ples were obtained with informed consent in accordance with fetal loss (26). Thum et al. (27) had found that elevated level of the Al-Kindi Teaching Hospital Declaration. Blood samples were drawn; serum was separated and stored at À20 C until testing. Cytokines (IL-6, IL-10, TNF-a and IFN-c) were measured by means of Enzyme Linked Immuno Table 1 Demographic data between infertile women and Sorbent Assay using US Biological Kit – USA. control group. Statistical analysis: Data was analyzed statistically using descriptive statistics: frequencies, mean and standard devia- Data Infertile women Control group p-Value tion. Considering the scattering of the collected data, the No. = 45 No. = 30 non-parameter Mann–Whitney test is used for measuring the X±SD X±SD differences between the studying groups. p-Values <0.05 were Age 32.2 ± 6.1 30.4 ± 9.1 >0.05 considered statistically significant. Calculations were per- BMI (kg/m2) 24.38 ± 5.92 23.32 ± 3.42 0.33 formed using Mini Tab statistical software program 13.20. 222 B.M. Mahdi

Table 2 The difference in the median levels of serum IL-6, IL-10, TNF-a and IFN-c (pg/ml) concentration between healthy and infertile women group. Values Infertile women Control group Mann–Whitey p-value No. = 45 No. = 30 Median Median (Minimum–Maximum) (Minimum–Maximum) IL-6 3.84 (0.48–79.3) 5.5 (2.5–65.0) 0.116 IL-10 18.09 (6.42–134.1) 6.7 (1.0–45.1) 0.002 TNFa 22.49 (6.56–62.76) 25.0 (10.0–33.78) 0.329 IFN-c 49.62 (25.55–188.51) 17.0 (12.0–25.0) 0.0001

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