INTRODUCTION:

Endometriosis is one of the most common gynaecological diseases. The disease will cause chronic pelvic pain, dysmenorrhea, severe dyspareunia, infertility and pelvic-organ dysfunction². Despite enhancements with the diagnosis and understanding of endometriosis, patients need laparoscopy for establishment of diagnosis^3,4.

An important general concept is that an altered immune related cells occurs due to local pelvic inflammatory process of endometriosis. Several immune cells are involved in the growth of endometriosis, however it is understood that T Lymphocytes and their related cytokines plays a vital role in disease development^5,6.

T lymphocytes stimulation and activation will contribute to the conduction, progression, and regulation of the immune responses. T helper 1 (Th1) subset within the peritoneal fluid (PF) in endometriosis women indicated higher levels of pro-inflammatory cytokines in several published papers.According to previous studies, women with endometriosis also had higher levels of Th1 cytokines like TNF-, IL-1, IL-6, IL-12, and IFN-γ^7,8. Infertility or subfertility which was observed in endometriosis patients might be caused due to toxic effects of these inflammatory cytokines on female reproductive system^9,10. On other side many studies have been discussed the role of Th2 responses and showed elevated levels of IL-4 and IL-10 in women with endometriosis^1,11,12.

IL-1 family cytokines are involved in the process of innate and adaptive immunity, Interleukin -18(IL-18) cytokine be an adherent to the IL-1 family recognised as interferon gamma (IFN-γ) in Kupffer cells and macrophages¹³. It makes a significant change in the inflammatory cascade and in the process of innate and adaptive immunity, it has the capability to persuade the production of IFN-γ in T lymphocytes and NK cells^13,14. IL-18 activates natural killer (NK) cells in order to protect against bacterial infections. However, IL-18 act together with IL-12 to stimulate the progress of the T helper response and a shift to theTh1^14,15.

Infertile patients with minor or mild endometriosis have been found to have a number of immunological abnormalities, including aberrant NK cell function^{16,17, 18}, a reduced ability of lymphocytes and macrophages to cause cytotoxicity¹⁵, and an excessive Th1/Th2 response^15,17. Several studies have been described as increased levels of cytokines in the peritoneal fluid of women with endometriosis¹.

Additionally, more cytokines have been predictable in the peritoneal fluid. Include: interleukins (IL-1, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, and IL-13), IFN-γ, tumor necrosis factor (TNF), and others^19,20,21,22were established in women with endometriosis. In the peritoneal fluid of women with endometriosis, The atypical expression of several cytokines were seen by the initiation of macrophage, such as IL-1, IL-6, IL-8, and TNF can contribute to an adverse peritoneal environment, motivates the growth of endometrial cells and the establishment of endometriosis^23,24,25.

Some investigators have studied the association between IL-18 and endometriosis. Arici et al¹⁴ reported significantly higher levels of IL-18 in the peritoneal fluid of patients with treated endometriosis when compared with control group of endometriosis without treatment (means±SEM, 91.1±6.5 vs 59.4±2pg/mL)¹⁴. Similar result was reported by Oku et al using immunohistochemically analysis (592±108 vs 260±55 pg/mL)^26,27,28. Furthermore, Zhang et al²⁹assessed the concentration of IL-18 in the peritoneal fluid and serum of women with endometriosis and reported that peritoneal concentration of IL-18 was significantly lower in patients with endometriosis (144.8pg/mL) than in women without endometriosis (653.4pg/mL) (Zhang Y et al 2005). Another author Luo et al³⁰found that down-regulation of IL-18 mRNA expression was observed in ectopic and eutopic endometrium of women with endometriosis. (Luo Q et al 2006), Fairbanks et al²⁹presented increased levels of IL-12 in the peritoneal fluid regardless of IL-18 levels in the patients with severe endometriosis (means±SEM, 142±23 vs 112±29 pg/mL).

Interleukin-4 and IL-10 are pleiotropic anti-inflammatory cytokines that is responsible mainly for defeating the pro-inflammatory location. Th2 cytokines plays a main role in Interleukin-4 and IL-10 family, whereas Th2 immune response is related with endometriosis. Interleukin 4 has both stimulatory and inhibitory effects on the inflammatory system. Higher concentration of IL-4 were reported in endometriotic tissues and also significant change in levels were observed in both plasma and peripheral blood mononuclear cells (PBMC) supernatants from patient with endometriosis. Some studies showed no association was found between IL-4 concentrations in women with endometriosis^31,32. Another current study in adolescent girls with endometriosis presented that immunological markers in serum and peritoneal fluid (PF) showed significantly higher concentrations of IL-4^33;34

Our evaluation aimed to explore a possible role of IL-4 and IL-18 in women with endometriosis and toinvestigate the concentration of serum levels of IL-4 and IL-18 in women with and without endometriosis

MATERIAL AND METHODS:

This study was approved by the ethics committee of the Sri Ramachandra Institute of Higher education and research. All participants signed a written informed consent prior to entering the study. The current study is a case control study comprising of women with endometriosis, compared with that of a control group of healthy women without endometriosis. The age of the study groups is 25 years to 46 years for the cases and controls. Forty women withendometriosiswere chosen for the study. The study enrolled individuals with surgically confirmed cases of endometriosis. Exclusion Criteria: Patients with inflammatory bowel disease, pelvic inflammatory disease, urinary tract infection were excluded from study. Fortycontrols were chosen with inclusion criteria who hadnormal vaginal deliveries, as well as no family history, clinical symptoms, or diagnosticevidence of endometriosis and excluded women with past or present history of endometriosis in Indian population.According to the revised American Society for Reproductive Medicine (rASRM) classification, the tables 1 represents the endometriosis type among the cases.Blood samples were taken from the study and control groups. After centrifugation, sera were immediately aliquoted and stored at −80°C until tested. Samples, taken from all patients were evaluated for IL-18 and IL-4, by a sandwich enzyme-linked immunosorbent assay.

Table 1: Characteristics of study subjects

Group	Endometriosis type		Description
Cases (N=40)	Mild	4	Endometriotic spots
	Moderate	12	Endometriotic spots
	Severe	24	Endometriotic cysts
Controls (N=40)	Not applicable		Not applicable

Enzyme-linked immunosorbent assay (ELISA):

The concentrations of IL-4 and IL-18 in sera were analysed using a quantitative sandwich enzyme immunoassay technique according to the manufacturer’s instructions (Immunoconcept India Pvt. Ltd). In brief, a monoclonal antibody for the specific cytokine was pre-coated onto a microtiter plate. Standards and samples were added into the wells, allowing adsorption of specific cytokine by the immobilized antibody. After washing away unbound substances, an enzyme-linked polyclonal antibody for the specific cytokine was added to the wells^35,36. After removal of unbound antibody-enzyme reagent, colour was developed and the optical density was read at 450nm. All cytokine concentrations (in picograms per millilitre) were determined by comparison with the standard curve.

Statistical Analysis:

Data was expressed as mean and standard deviation. The collected data was analysed with IBM SPSS Statistics for Windows, Version 23.0.0rmonk, NY: IBM Corp). To describe about the data descriptive mean, median, IQR and S.D were used. To find the significant difference between the bivariate samples in Independent groups the Mann-Whitney U test was used. In the above statistical tool the probability value 0.05 is considered as significant level.

Ethical Approval:

The study was approved by the ethics committee (Ref: IEC-NI/17/APR/59/38) of the SRI RAMACHANDRA Institute of Higher Education and Research (DU).

RESULTS:

The present study was performed 40 women with endometriosis and 40 women without endometriosis. The mean of age in endometriosis and non-endometriosis women were 31.2±3.8 and 32.9±5 years, respectively. The levels of IL-4 and IL-18 cytokines were estimated in serum samples, and compared between the study and control groups using the ELISA method as described earlier here.

Table 2 represents the results of cytokine assays in the sera of both endometriosis and non-endometriosis groups. As shown, there were significant differences between two studied groups regarding the concentration of IL-4 and IL-18 cytokines.

Themeans ± SD of the serum levels of IL-4 in women with endometriosis was89.63±16.30pg/mL, and in the control group, the serum level of IL-4 was 21.68±10.43 pg/mL

The means±SD of the serum levels of IL-18 in women with endometriosis was170.05±18.74pg/mL, and in the control group, the serum level of IL-18was76.30±13.58 pg/mL

Table 2: Level of Serum Cytokines in Study Groups.

Serum cytokine

(pg/ml)

Endometriosis group

Mean (SEM)

Non-endometriosis group

Mean (SEM)

p-value

IL-4

89.6374 (2.5)

21.68658 (1.64)

< 0.05*

IL -18

170.0529 ( 2.9)

76.3029 (2.14)

< 0.05*

Table 3 represent the descriptive analysis of both IL4 and IL-18 study group. There is a statistically significant difference found between non endometriosis and endometriosis in both IL-4 and IL-18 with P value 0.0005

Table 3: Descriptive analysis of IL-4 and IL-18

		Non-endometriosis group	Endometriosis group	P value
IL-4	Mean	21.69	89.64	0.0005
	Median	19.83	87.30
	Std. Deviation	10.43	16.30
	Range	35.63	64.51
	Interquartile Range	15.39	28.49
IL-18	Mean	76.30	170.05	0.0005
	Median	76.50	171.12
	Std. Deviation	13.58	18.75
	Range	48.08	79.42
	Interquartile Range	19.47	35.87

(a) (b)

Figure 1: Concentration of Serum levels a) represents Serum levels of IL-4 in Serum in women with endometriosiscompared with control samples and b) representsSerum levels of IL-18 in Serum in women with endometriosis compared with control samples

DISCUSSION:

Endometriosis is a common gynaecological disease, with many theories on the endometriosis pathogenesis in association with the regulation of cell multiplication and neo-angiogenesis. Many cytokines are associated with the pathogenesis of endometriosis, mainly growth factors and pro-inflammatory or anti-inflammatory cytokines involved. It has been suggested that in retrograde menstruation, the altered immunological system may result in endometriosis owing to establishment of peritoneal implants^37,38,39. A role of cytokines²⁶was emphasized with some interleukins showing increased levels in patients with endometriosis ^12,30,31. Previous studies suggested that endometriosis may be considered as a type of autoimmune disease^14,41. Furthermore, circulating monocytes presented an improved stimulation in women with endometriosis. Levels of TNF-α, IL-6 and IL-8 production was increased in affected cellswhen compared to cells of unaffected patients^41,42.

Interleukin-18 (IL-18) is a cytokine which is produced by activated macrophages. While it shares purposeful properties with IL-12 and structural resemblances with the IL-1 family, with effects that are impartial of both. Th1 immunological response is encouraged by IL-18 while making the production of IFN-γ by macrophages, T lymphocytes and NK cells^43,44,45,46. Till date, several studies have evaluated the serum level of IL-18 in patients with endometriosis with contradictory results ^12,25,30,45. Zhang et al⁴⁶ found that there is nocorrelationbetween peritoneal and serum concentrations of IL-18.While other reports did not estimate this correlation. Podgaec et al¹²reported an increased level of IFN-γ and IL-10 in patients with endometriosis (Podgaec S et al 2007) with an occurrence of IL-4 and IL-10 when comparing the ratio between cytokine levels, which indicates a possible shift towards Th2 immune responses.

On the other hand, Bellelis et al reported that cytokine gene polymorphisms will have an effect on serum levels of cytokines by influencing transcriptional regulation which shows the genetic and hereditary basis for endometriosis⁴⁷.

The present study has investigated a possible association of both IL-4 and IL-18 serum levels in patients with endometriosis. The results showed a significantly higher serum level of both IL-4 and IL-18 in patients with endometriosis compared to healthy controls, thus suggesting an association between the IL-4 serum levels and endometriosis as well as an association between IL-18 serum levels and endometriosis

Several studies were performed in the past decade indicating that there are changes in the peritoneal fluid cytokine and serum cytokines levels of endometriotic patients. Concentration of peritoneal fluid and serum level of IL-4 showed significantly higher value in the recent study³⁴. Furthermore, Antsiferova et al¹. have been reported that the intra-cellular mRNA expression and synthesis of IL-4 and IL-10 in peripheral lymphocytes have been associated with endometriosis development, even in ectopic endometrium of women with endometriosis. Similar changes were observed in IL-4⁴⁸, and an enhanced production of Il-4 in peritoneal fluid of patients with endometriosis which normalized after hormone therapy^49,50. Some studies were reported that there is no association in serum and PF IL-4 levels between normal and early- and late-stage endometriosis⁵¹. Our results are confirming some of the previous studies as we found an increased IL-4 and Il-18 serum level in patients with endometriosis.

In conclusion, we found that IL-4 and IL-18 cytokines serum levels are significantly higher in women with endometriosis compared to healthy controls. Cytokines play their specific roles in pathogenesis of endometriosis. IL-4 and IL-18 cytokines could be used as a potential biomarker for non-invasive test for endometriosis. Further studies are needed with more data to determine their role as a biomarker for endometriosis.

ABBREVIATIONS:

IL: Interleukin, ELISA: Enzyme-linked immunosorbent assay; IFN-γ: Interferon gamma; NK: Natural killer; TNF-α: Tumor necrosis factor –alpha; Th: T helper; SEM: Standard Error of the mean; pg/mL: Picograms per millilitre; PBMC: peripheral blood mononuclear cells; PF: Peritoneal fluid; IQR: Interquartile range; S.D: Standard deviation; nm: nanometer; SPSS: Statistical Package for the Social Sciences; IBM: International Business Machines.

DISCLOSURE STATEMENT:

No potential conflict of interest was reported by the authors.

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Received on 13.08.2022 Modified on 02.10.2022

Research J. Pharm. and Tech 2023; 16(7):3120-3124.

DOI: 10.52711/0974-360X.2023.00513