{"paper_id":"37352a82-ae1b-4b36-8721-3b532802c6b0","body_text":"Ragab et al. \nEgyptian Journal of Medical Human Genetics           (2022) 23:72  \nhttps://doi.org/10.1186/s43042-022-00285-x\nRESEARCH\nIncreased expression of IL-37 correlates \nwith TNF-α levels and disease stage \nin endometriosis patients\nDina Ragab1* , Ahmed Abbas2 and Ramy Salem1 \nAbstract \nBackground: IL-37 is an anti-inflammatory cytokine that increases in several inflammatory diseases with the main \ninducing signal for its production being pro-inflammatory cytokines like TNF-α. We aimed to assess the correlation \nbetween peritoneal fluid levels of IL-37 and TNF-α in endometriosis patients and investigate their association with \ndisease stage. Levels of IL-37 and TNF-α were assessed in peritoneal fluid of 50 patients with endometriosis and 23 \nendometriosis-free females using enzyme-linked immunosorbent assay. We also assessed serum levels of IL-37 using \nenzyme-linked immunosorbent assay and expression of IL-37 mRNA in peritoneal fluid cells using polymerase chain \nreaction.\nResults: Peritoneal fluid levels of IL-37 and TNF-α were higher in endometriosis patients than in control females. Also, \nlevels were higher in patients with late endometriosis than patients with early endometriosis. In addition, serum levels \nof IL-37, as well as IL-37 mRNA expression in peritoneal fluid cells, were higher in patients than controls. In endome-\ntriosis patients, peritoneal fluid levels of IL-37 positively correlated with levels of TNF-α.\nConclusion: Collectively, our results show increased levels of the anti-inflammatory cytokine IL-37 in endome-\ntriosis patients that correlate with levels of the pro-inflammatory cytokine TNF-α, one of the main signals for IL-37 \nproduction.\nKeywords: IL-37, TNF-α, Peritoneal fluid, Endometriosis\n© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.\nBackground\nEndometriosis is a disease characterized by the pres -\nence of functioning endometrial tissue, both glandular \nepithelium, and stroma, outside of the uterus [1]. It is a \ncommon disease that affects around 2–10% of females \n[2]. Patients typically complain of abdominal pain, dys -\nmenorrhea, dyspareunia, and infertility, however, some \npatients may be asymptomatic and are accidentally dis -\ncovered during laparoscopy for any other reason [3]. \nEndometriosis can occur in a variety of locations, the \nmost common of which are the ovary, rectovaginal \nseptum, Douglas pouch, and uterosacral ligaments. It can \nsometimes occur in the vagina, rectum, fallopian tubes, \nuterine cervix, or the urinary tract [4]. Symptoms associ -\nated with endometriosis have an impact on the patient’s \nphysical, psychological, and social well-being [5].\nThe exact etiology of endometriosis is not fully eluci -\ndated, however multiple theories have been proposed, \namong which are environmental factors, hormones, \ndysregulated immunity, inflammatory factors as well as \ngenetic and epigenetic factors [6]. One widely accepted \ntheory is retrograde menstruation followed by implan -\ntation of endometrial fragments. A growing body of lit -\nerature indicates that the survival of endometrial tissue is \nenhanced by a concurrently altered immune surveillance \nthat allows the survival of the implanted endometrial tis -\nsue [7].\nOpen Access\nEgyptian Journal of Medical\nHuman Genetics\n*Correspondence:  dinaragab@med.asu.edu.eg\n1 Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, \nEgypt\nFull list of author information is available at the end of the article\n\nPage 2 of 7Ragab et al. Egyptian Journal of Medical Human Genetics           (2022) 23:72 \nInterleukin-37 (IL-37) is an anti-inflammatory cytokine \nand one of the members of the IL-1 family. IL-37 is mainly \nexpressed in circulating monocytes, tissue macrophages, \ndendritic cells, tonsil B cells, and plasma cells [8]. IL-37’s \nanti-inflammatory function is primarily achieved by sup -\npressing innate immunity [9]. Expression and production \nof IL-37 are increased in response to exposure to various \ntoll-like receptor ligands, as well as, pro-inflammatory \ncytokines including IL-1, TNF-α, IL-18, and IFN-γ [8]. \nFurthermore, data from multiple studies show that IL-37 \nplays a role in controlling the inflammatory process in a \nvariety of inflammatory diseases [10–17].\nAs an anti-inflammatory cytokine, IL-37 is suggested \nto play a role in endometriosis. Women with endome -\ntriosis had higher IL-37 mRNA expression in ectopic \nand eutopic endometrium [18] as well as higher serum \nand intraperitoneal fluid levels [19]. In mice, IL-37 over -\nexpression inhibited endometrial stromal cells prolif -\neration and adhesion [20]. The relationship between \nIL-37 and proinflammatory cytokines in endometriosis \npatients has not been investigated before. Because pro-\ninflammatory cytokines, such as TNF-α, are considered \nto be the primary stimulus for increased IL-37 expres -\nsion and production [21], herein, we sought to examine \nthe relationship between levels of IL-37 and levels of \nTNF-α in peritoneal fluid of endometriosis patients. We \nalso assessed serum IL-37 levels as well as the expression \nof IL-37 mRNA in peritoneal fluid cells of endometriosis \npatients.\nMethods\nStudy participants\nThe study included 73 females recruited from the Gyne -\ncology and Obstetrics Department at the Faculty of \nMedicine, Ain Shams University. All study participants \nhad regular menstrual cycles and were in the menstrual \ncycle’s proliferative phase (according to the last men -\nstrual period date). Females who had received hormonal \ntreatment in the previous 6 months or who had any con -\ncomitant autoimmune disease, endometrial hyperplasia, \nendometritis, endometrial cancer, or adenomyosis were \nexcluded. The patients’ group included 50 endometriosis \npatients who were diagnosed through histopathological \nexamination following laparoscopy. The revised Ameri -\ncan Fertility Society (rAFS) classification of endometrio -\nsis was used to assess endometriosis staging and scoring. \nThe rAFS score was used to categorize patients into four \nstages: Stage I (minimal; rAFS score 1–5), Stage II (mild; \nrAFS score 6–15), Stage III (moderate; rAFS score 16–40) \nand Stage IV (severe; rAFS score > 40). Endometriosis \npatients in stages I and II were grouped as “early endo -\nmetriosis group” while those in stage III and stage IV \nwere grouped as “late endometriosis group” . As a control \ngroup, 23 age-matched females, who underwent laparos -\ncopy for diagnostic reasons, tubal disconnection, ovarian \ncystectomy, ovarian drilling, and who were confirmed to \nnot have endometriosis during laparoscopy ± histologi-\ncal examination if needed, were recruited to the study. \nBefore taking part in the study, each participant provided \nwritten informed consent.\nSamples\nTwo milliliters (2  mL) of venous blood were collected \ninto vacutainer tubes (gel type), and the serum was cen -\ntrifuged at 3000  rpm for 15  min before being stored at \n− 80  °C until it was used later to measure serum IL-37 \nlevels. Peritoneal fluid (2 mL) was collected at the begin -\nning of the laparoscopy from the pouch of Douglas in a \nsterile centrifuge tube. After centrifuging the sample \nat 3000  rpm for 15  min, the supernatant was stored at \n− 80  °C until used to assess peritoneal fluid IL-37 and \nTNF-α levels, while cell pellets were stored in RNA later \n(Qiagen, Germany) at − 80  °C till used later in mRNA \nextraction.\nAssessment of IL‑37 and TNF‑α levels\nLevels of IL-37 in both serum and peritoneal fluid were \nmeasured using an enzyme-linked immunosorbent assay \n(ELISA) kit provided by Elabscience, USA, while levels \nof TNF-α in the peritoneal fluid were measured using an \nELISA kit provided by R&D Systems, UK.\nAssessment of IL‑37 mRNA expression\nmRNA extraction\nRNeasy Mini Kit (Qiagen, Germany) was used to extract \nRNA from peritoneal fluid cells. Reverse-transcription of \nRNA into complementary DNA was done using Quanti -\nTect Reverse Transcription kit (Qiagen, Germany) by \nincubating a total volume of 14 uL containing 1ug RNA, \n2  uL gDNA wipe-out buffer, and RNase free water for \n2  min at 42  °C. Then 1  uL reverse transcriptase, 4  uL \nRT buffer, and 1uL RT primer mix were added to reach \na total volume of 20 uL. The mixture was incubated for \n15 min at 42 °C followed by 3 min at 95 °C.\nReal‑time PCR\nTaqMan Gene Expression Master Mix (Applied Biosys -\ntems, USA) and TaqMan Gene Expression Assay sets \n(Applied Biosystems, USA) were used for gene expres -\nsion PCR analysis of IL-37 and GAPDH as the normal -\nizing house-keeping gene. The reaction volume (total \n20 uL) included 10 uL Master Mix, 1 uL Taqman assay, \n7  uL nuclease-free water, and 2  uL cDNA. Rotorgene \nQPCR System was used for amplification according to \nthe following protocol: initial activation for 10  min at \n95  °C, followed by 40 cycles of denaturation for 15  s at \n\nPage 3 of 7\nRagab et al. Egyptian Journal of Medical Human Genetics           (2022) 23:72 \n \n95  °C followed by annealing and extension for 1  min at \n60  °C. The comparative CT method (also known as the \n 2−ΔCT method) was used to calculate IL-37 mRNA rela -\ntive expression by normalizing to GAPDH.\nStatistical analysis\nFor statistical analysis, Graph Pad Prism 5 (San Diego, \nCA, USA) was used. The median and interquartile range \nwere used to present quantitative data, while number \nand percentage were used to present categorical data. \nTo compare groups, the Mann–Whitney test was used. \nSpearman’s correlation was used to determine the degree \nof correlation between parameters. A p value of < 0.05 \nwas deemed statistically significant.\nResults\nClinical characteristics of study participants\nThe study included 50 patients with endometriosis, with \na mean age of 29.7 ± 6.2  years. Patients were classified \naccording to their rAFS stage: seven had stage I endome -\ntriosis, nineteen had stage II endometriosis, nineteen had \nstage III endometriosis, and five had stage IV endome -\ntriosis. Control samples were collected from 23 women \nwho did not have endometriosis and had mean age of \n30.9 ± 5.1 years (Table 1).\nElevated IL‑37 levels in endometriosis patients\nWe first wanted to look into IL-37 levels and expression \nin Egyptian endometriosis patients because they had \nnever been investigated before. And, before assessing \nthe correlation of IL-37 with TNF-α, we wanted to find \nout if IL-37 levels were higher in endometriosis patients \ncompared to control females. Endometriosis patients \nshowed significantly higher serum IL-37 levels compared \nto controls (p < 0.0001) (Fig.  1A). Furthermore, perito -\nneal fluid samples of endometriosis patients showed sig -\nnificantly higher IL-37 levels compared to the peritoneal \nfluid of controls (p < 0.0001) (Fig. 1B).\nHigher IL‑37 levels in late endometriosis stages\nTo evaluate if higher IL-37 levels were related to endome-\ntriosis stage, patients were divided into two groups based \non their r-AFS stage: early endometriosis (stages I and \nII) and late endometriosis (stages III and IV), and IL-37 \nlevels were compared between both groups. Patients \nwith late stages of endometriosis (n = 24) had signifi -\ncantly higher serum IL-37 levels compared to patients \nwith early stages of endometriosis (n = 26) (p = 0.0018) \n(Fig.  2A). Furthermore, IL-37 levels in peritoneal fluid \nwere significantly higher in patients with late stage endo -\nmetriosis compared to patients with early stage endome -\ntriosis (p = 0.0001) (Fig. 2B).\nIncreased IL‑37 mRNA expression in endometriosis \npatients\nReal-time PCR was used to look at the expression of \nIL-37 mRNA in peritoneal fluid cells. IL-37 mRNA rela -\ntive expression was higher in peritoneal fluid cells of \nendometriosis patients compared to cells from controls \n(p < 0.0001) (Fig.  3A). In addition, late endometriosis \npatients had significantly higher IL-37 mRNA relative \nexpression than early endometriosis patients (p = 0.0017) \n(Fig. 3B).\nTable 1 Demographical and clinical characteristics of endometriosis patients and controls\nIQR interquartile range, NA not applicable, rAFS revised American Fertility Society\nEndometriosis patients (n = 50) Controls (n = 23)\nAge in years, mean ± SD 29.7 ± 6.2 30.9 ± 5.1\nParity, n (%)\n P0 38 (76%) 15 (65.2%)\n P1 6 (12%) 5 (21.7%)\n P2 6 (12%) 3 (13.1%)\nrAFS score for endometriosis, median (IQR) 14 (10–26) NA\nrAFS stage for endometriosis, n (%)\n Stage I 7 (14%) NA\n Stage II 19 (38%)\n Stage III 19 (38%)\n Stage IV 5 (10%)\nSerum IL-37 (pg/mL), median (IQR) 128.1 (93.9–198.7) 64.6 (52.7–94.3)\nPeritoneal fluid IL-37 (pg/mL), median (IQR) 146.2 (106.1–194.4) 75.5 (61.8–108.2)\nIL-37 mRNA expression,  (2−ΔCT ) 0.0239 (0.01393–0.03218) 0.0029 (0.0017–0.0052)\nPeritoneal fluid TNF-α (pg/mL), median (IQR) 55.55 (39.7–63.5) 15.6 (12.8–19.3)\n\nPage 4 of 7Ragab et al. Egyptian Journal of Medical Human Genetics           (2022) 23:72 \nHigh peritoneal fluid TNF‑α levels in endometriosis \npatients\nEndometriosis patients showed significantly higher \nTNF-α levels in their peritoneal fluid compared to con -\ntrols (p  < 0.0001) (Fig. 4A). Moreover, patients with late \nstages of endometriosis showed significantly higher \nperitoneal fluid TNF-α levels compared to patients with \nearly stages of endometriosis (p  = 0.0006) (Fig. 4 B).\nIL‑37 levels correlate with TNF‑α levels\nTNF-α, among other pro-inflammatory cytokines, \neffectively induces the expression of IL-37 [20]. The \nFig. 1 Elevated serum (A) and peritoneal fluid (B) levels of IL-37 in endometriosis patients compared to control females\nFig. 2 Higher levels of serum (A) and peritoneal fluid (B) IL-37  in late stages of endometriosis\nFig. 3 Higher relative expression of IL-37 mRNA in endometriosis patients compared to control females (A) and in late stages of endometriosis \ncompared to early stages (B)\n\nPage 5 of 7\nRagab et al. Egyptian Journal of Medical Human Genetics           (2022) 23:72 \n \nrelationship between IL-37 and TNF-α in endometriosis \npatients has not been previously investigated. To address \nthis point, we examined the correlation between levels of \nIL-37 and levels of TNF-α in the peritoneal fluid of endo -\nmetriosis patients. IL-37 levels positively correlated with \nTNF-α levels in peritoneal fluid (r s = 0.7221, p < 0.0001) \n(Fig. 5).\nDiscussion\nAccording to emerging evidence, immune cells and \ncytokines play a profound role in the immuno-patho -\ngenesis of endometriosis. Endometriosis is, in fact, \nthought to be an estrogen-dependent chronic inflamma -\ntory condition [7, 22]. Supporting this concept are stud -\nies focusing on macrophages and natural killer cells in \nboth ectopic endometrial tissue and the peritoneal fluid, \nsuggesting that ectopic endometrial tissue contains an \nincreased number of immune cells that produce a vari -\nety of products, including several cytokines and growth \nfactors that enhance ectopic tissue implantation and con-\ntribute to the inflammation and fibrosis that result from \nendometriosis [23, 24]. Cytokines are considered among \nthe key players that can participate in modulating the \nimplantation milieu and participating in the inflamma -\ntory process that is associated with endometriosis [25].\nIn the present study, we report higher serum and peri -\ntoneal fluid IL-37 levels in endometriosis patients with \nhigher levels in later endometriosis stages compared to \nearly stages. Similar findings were reported by Kaabachi \net  al. [19] who studied levels of IL-37 in 30 Tunisian \nendometriosis patients and found higher IL-37 levels \nin both serum as well as peritoneal fluid samples. Also, \nJiang et  al. [26] found comparable results in a group of \n40 Chinese females with endometriosis compared to \n32 controls. Meanwhile, in a study involving 27 Chi -\nnese endometriosis patients and 36 controls, Fan et  al. \n[27] reported higher serum IL-37 in endometriosis \npatients but no difference in peritoneal fluid IL-37 lev -\nels. IL-37 tends to increase in inflammatory conditions \nin an attempt to dampen the inflammatory process [28]. \nAdministration of recombinant IL-37 in endometriosis \nmice resulted in a significant decrease in endometriotic \nlesion size and weight and also lowered pro-inflamma -\ntory cytokine expression as well as vascular endothelial \ngrowth factor and soluble adhesion molecules, in peri -\ntoneal fluid of endometriosis mice [20]. Furthermore, in-\nvitro transfection of endometrial stromal cells with IL-37 \nRNA was reported to suppress endometrial stromal cell \nproliferation, adhesion, migration, and invasion [20]. \nConsequently, it is possible to postulate that IL-37 might \nplay a potential role in the immune response that occurs \nin endometriosis.\nEvidence is accumulating that IL-37 plays a role in \nlimiting excessive inflammation. IL-37 levels have been \nfound to rise in a variety of inflammatory conditions \nincluding osteoarthritis [10], rheumatoid arthritis [11], \nsystemic lupus erythematosus [12], atopic dermatitis \n[13], and inflammatory bowel diseases [16]. Furthermore, \nthe potential use of IL-37 as an anti-inflammatory agent \nin chronic inflammatory conditions has been investigated \nFig. 4 Higher levels of TNF-α in peritoneal fluid of endometriosis patients compared to control females (A) and in late stages of endometriosis \ncompared to early stages (B)\nFig. 5 Levels of IL-37 in peritoneal fluid of endometriosis patients \npositively correlated with TNF-α levels\n\nPage 6 of 7Ragab et al. Egyptian Journal of Medical Human Genetics           (2022) 23:72 \nin animals models, where treatment with IL-37 in allergic \nrhinitis murine models alleviated  allergic inflammation \nthrough repressing STAT6 and STAT3  signalling path -\nways [ 29]. Treatment with recombinant IL-37 also sup -\npressed joint inflammation in mouse models of arthritis \n[30]. IL-37b gene transfer enhanced the therapeutic \nefficacy of mesenchymal stem cells in dextran sulfate \nsodium-induced colitis mice through inducing regulatory \nT cells and myeloid-derived suppressor cells and regulat -\ning cytokine production [31].\nOur results show higher expression of IL-37 mRNA \nin endometriosis patients compared to controls, with \nhigher levels in later endometriosis stages compared to \nearly stages. IL-37 expression increases in response to \nthe pro-inflammatory cytokines e.g., IL-1, IL-18, TNF-\nα, and IFN-γ [21]. However, the relationship between \nthese cytokines and IL-37 in endometriosis patients has \nnot been studied before. Our results show higher levels \nof TNF-α in peritoneal fluid of endometriosis patients \nwith higher levels in late endometriosis compared to \nearly endometriosis explaining the high IL-37 levels and \nexpression observed in endometriosis patients in our \nstudy. Furthermore, in our study, IL-37 levels in perito -\nneal fluid were found to positively correlate with TNF- \nlevels. Several studies have reported increased TNF-α in \nthe peritoneal fluid of endometriosis patients [32–34]. \nMeanwhile, increased IL-37 mRNA expression in perito -\nneal fluid cells was also reported by Kaabachi et al. [19]. \nNevertheless, Jiang et  al. [18] reported higher mRNA \nexpression in ectopic endometrial biopsies as well as \neutopic endometrial biopsies in endometriosis patients \ncompared to eutopic endometrium from females without \nendometriosis.\nTo the best of our knowledge, this is the first study to \nlook at the relationship between TNF-α and IL-37 levels \nin endometriosis patients. This is also the first study to \nassess IL-37 levels and expression in Egyptian endome -\ntriosis patients. One limitation of the present study is \nthe relatively small number of patients included. Further \nresearch on a larger scale of patients as well as further \nfollow-up studies are needed to assess the levels of IL-37 \nduring endometriosis progression and the possible cor -\nrelation of IL-37 levels with levels of TNF-α and other \ncytokines throughout the course of the disease.\nConclusions\nIn conclusion, we report higher serum and perito -\nneal fluid IL-37 levels as well as higher peritoneal fluid \nTNF-α levels in endometriosis patients with a positive \ncorrelation between TNF-α and IL-37 levels. Our data \nin addition to previous reports highlight the poten -\ntial importance of IL-37 in the immune process during \nendometriosis.\nAbbreviations\nIL-37: Interleukin 37; rAFS: Revised American Fertility Society; TNF-α: Tumor \nnecrosis factor α.\nAcknowledgements\nNot applicable.\nAuthors’ contributions\nDR, AA designed the study. AA collected the samples, collected patients’ \nclinical data and staged the patients. DR, RS carried out the laboratory work, \nanalyzed the data and carried out statistical analysis. DR, RS drafted the paper. \nAA revised the paper. All authors read and approved the final manuscript.\nFunding\nNone.\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from \nthe corresponding author on reasonable request.\nDeclarations\nEthics approval and consent to participate\nThe study protocol was approved by the ethical committee of the Faculty \nof Medicine, Ain Shams University. Ethical approval reference number (FWA \n000017585). Written informed consent was taken from all subjects before \nparticipation in this study.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare that they have no competing interests.\nAuthor details\n1 Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt. \n2 Obstetrics and Gynecology, Faculty of Medicine, Ain Shams University, Cairo, \nEgypt. \nReceived: 13 February 2022   Accepted: 11 March 2022\nReferences\n 1. Agarwal S, Chapron C, Giudice L, Laufer M, Leyland N, Missmer S et al \n(2019) Clinical diagnosis of endometriosis: a call to action. Am J Obstet \nGynecol 220(4):354.e1-354.e12\n 2. Shafrir A, Farland L, Shah D, Harris H, Kvaskoff M, Zondervan K et al (2018) \nRisk for and consequences of endometriosis: a critical epidemiologic \nreview. Best Pract Res Clin Obstet Gynaecol 51:1–15\n 3. Kor E, Mostafavi S, Mazhin Z, Dadkhah A, Kor A, Arvanagh S et al (2020) \nRelationship between the severity of endometriosis symptoms (dys-\npareunia, dysmenorrhea and chronic pelvic pain) and the spread of the \ndisease on ultrasound. BMC Res Notes 13(1):546\n 4. Mehedintu C, Plotogea M, Ionescu S, Antonovici M (2014) Endometriosis \nstill a challenge. J Med Life 7(3):349–357\n 5. Kajiyama H, Suzuki S, Yoshihara M, Tamauchi S, Yoshikawa N, Niimi K et al \n(2019) Endometriosis and cancer. Free Radic Biol Med 133:186–192\n 6. Chapron C, Marcellin L, Borghese B, Santulli P (2019) Rethinking mecha-\nnisms, diagnosis and management of endometriosis. Nat Rev Endocrinol \n15(11):666–682\n 7. Vallve-Juanico J, Houshdaran S, Giudice L (2019) The endometrial \nimmune environment of women with endometriosis. Hum Reprod \nUpdate 25(5):565–592\n 8. Su Z, Tao X (2021) Current understanding of IL-37 in human health and \ndisease. Front Immunol 12:696605\n\nPage 7 of 7\nRagab et al. Egyptian Journal of Medical Human Genetics           (2022) 23:72 \n \n 9. Jia H, Liu J, Han B (2018) Reviews of Interleukin-37: functions, receptors, \nand roles in diseases. Biomed Res Int 2018:3058640\n 10. Ding L, Hong X, Sun B, Huang Q, Wang Z, Liu X et al (2017) IL-37 is associ-\nated with osteoarthritis disease activity and suppresses proinflammatory \ncytokines production in synovial cells. Sci Rep 7:11601\n 11. Ragab D, Mobasher S, Shabaan E (2019) Elevated levels of IL-37 correlate \nwith T cell activation status in rheumatoid arthritis patients. Cytokine \n113:305–310\n 12. Wu G, Li H, Wang J, Leng R, Wang D, Ye D (2016) Elevated plasma \ninterleukin-37 levels in systemic lupus erythematosus patients. Lupus \n25(12):1377–1380\n 13. Fujita H, Inoue Y, Seto K, Komitsu N, Aihara M (2013) Interleukin-37 is \nelevated in subjects with atopic dermatitis. J Dermatol Sci 69(2):173–175\n 14. Chen B, Huang K, Ye L, Li Y, Zhang J, Fan X et al (2015) Interleukin-37 is \nincreased in ankylosing spondylitis patients and associated with disease \nactivity. J Transl Med 13:36\n 15. Ballak D, Van Diepen J, Moschen A, Jansen H, Hijmans A, Groenhof G et al \n(2014) IL-37 protects against obesity-induced inflammation and insulin \nresistance. Nat Commun 5:4711\n 16. Li Y, Wang Y, Liu Y, Wang Y, Zuo X, Li Y et al (2014) The possible role of the \nnovel cytokines IL-35 and IL-37 in inflammatory bowel disease. Mediat \nInflamm 2014:136329\n 17. Zhang L, Zhang J, Gao P (2017) The potential of interleukin-37 as an \neffective therapeutic agent in asthma. Respir Res 18:192\n 18. Jiang J, Deng Y, Xue W, Zheng T, Sun A (2016) Increased expression of \ninterleukin 37 in the eutopic and ectopic endometrium of patients with \novarian endometriosis. Reprod Sci 23:244–248\n 19. Kaabachi W, Kacem O, Belhaj R, Hamzaoui A, Hamzoui K (2017) Interleu-\nkin-37 in endometriosis. Immunol Lett 185:52–55\n 20. Jiang J, Kenan Y, Jiang Z, Xue M (2018) IL-37 affects the occurrence and \ndevelopment of endometriosis by regulating the biological behavior \nof endometrial stromal cells through multiple signaling pathways. Biol \nChem 399(11):1325–1337\n 21. Nold M, Nold-Petrv C, Zepp J, Palmer B, Bufler P , Dinarello C (2010) IL-37 is \na fundamental inhibitor of innate immunity. Nat Immunol 11:1014–1022\n 22. Lousse J, Van Langendonckt A, Defrere S, Ramos R, Colette S, Donnez J \n(2012) Peritoneal endometriosis is an inflammatory disease. Front Biosci \n4:23–40\n 23. Bulletti C, Coccia M, Battistoni S, Borini A (2010) Endometriosis and infer-\ntility. J Assist Reprod Genet 27:441–447\n 24. Gazvani R, Templeton A (2002) Peritoneal environment, cytokines and \nangiogenesis in the pathophysiology of endometriosis. Reproduction \n123(2):217–226\n 25. Lin Y, Chen Y, Chang H, Au H, Tzeng C, Huang Y (2018) Chronic niche \ninflammation in endometriosis-associated infertility: current understand-\ning and future therapeutic strategies. Int J Mol Sci 19(8):2385\n 26. Jiang J, Jiang Z, Xue M (2019) Serum and peritoneal fluid levels of \ninterleukin-6 and interleukin-37 as biomarkers for endometriosis. Gynecol \nEndocrinol 35(7):571–575\n 27. Fan Y, Chen H, Chen W, Liu Y, Fu Y, Wang L (2018) Expression of inflamma-\ntory cytokines in serum and peritoneal fluid from patients with different \nstages of endometriosis. Gynecol Endocrinol 34(6):507–512\n 28. Jia H, Liu J, Han B (2018) Reviews of Interleukin-37: functions, receptors \nand roles in diseases. BioMed Res Int 2018:3058640\n 29. Wang J, Shen Y, Li C, Liu C, Wang Z, Li Y et al (2019) IL-37 attenuates \nallergic process via STAT6/STAT3 pathways in murine allergic rhinitis. Int \nImmunopharmacol 69:27–33\n 30. Cavalli G, Koenders M, Kalabokis V, Kim J, Tan A, Garlanda C et al (2016) \nTreating experimental arthritis with the innate immune inhibitor \ninterleukin-37 reduces joint and systemic inflammation. Rheumatology \n55(12):2220–2229\n 31. Wang W, Dong K, Zhou L, Jiao G, Zhu C, Li W et al (2015) IL-37b gene \ntransfer enhances the therapeutic efficacy of mesenchymal stromal cells \nin DSS-induced colitis mice. Acta Pharmacol Sin 36:1377–1387\n 32. Richter O, Dorn C, Rösing B, Flaskamp C, Urlich U (2005) Tumor necrosis \nfactor alpha secretion by peritoneal macrophages in patients with endo-\nmetriosis. Arch Gynecol Obstet 271(2):143–147\n 33. Wang X, Ma Z, Song N (2018) Inflammatory cytokines IL-6, IL-10, IL-13, \nTNF-α, and peritoneal fluid flora were associated with infertility in \npatients with endometriosis. Eur Rev Med Pharmacol Sci 22(9):2513–2518\n 34. Shamkhi J, Abbas A, Al-Deen T (2019) Estimation of TLR-4 and cytokines \nlevels (interleukin-1 Beta, interleukin-8, tumor necrosis factor) in serum \nand peritoneal fluid of endometriosis women. Indian J Public Health Res \nDev 10(4):1666–1672\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}