{"paper_id":"6a32688f-239f-4274-8bad-4dcd545f9fa9","body_text":"Abstract\nThe purpose of this study was to test the hypothesis that different cytokine profiles may exist in the follicular fluid of endometriosis (EM) patients undergoing in vitro fertilization (IVF), as these differences may provide insights into the pathogenesis of the disease. This was a cross-sectional study conducted at the reproductive center of a medical university hospital. The study included 49 patients receiving IVF. 20 infertile women with proven EM and 29 women without diagnosed EM (control group) were evaluated. Follicular fluid (FF) and serum were collected at the time of follicle aspiration and the concentrations of 38 cytokines were determined by multiplexed immunoassay. The results indicated that the levels of IL-4, IL-13, IL-3 and IL-1α were significantly increased in the FF of women with EM, while levels of IFN-γ, IL-17A, MDC and MIP-1α were decreased compared with in the control subjects. In conclusions, the immune microenvironment of the FF in patients with EM is altered. This may contribute to the pathologic mechanism responsible for the poor outcome of IVF in patients with EM.\nSimilar content being viewed by others\nReferences\nSampson JA (1927) Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol 3(2):93–110\nDu YB, Gao MZ, Shi Y, Sun ZG, Wang J (2013) Endocrine and inflammatory factors and endometriosis-associated infertility in assisted reproduction techniques. Arch Gynecol Obstet 287(1):123–130\nDa Broi MG, Jordão AA Jr, Ferriani RA, Navarro PA (2018) Oocyte oxidative DNA damage may be involved in minimal/mild endometriosis-related infertility. Mol Reprod Dev 85(2):128–136\nGarrido N, Navarro J, Garcia-Velasco J, Remoh J, Pellicer A, Simon C (2002) The endometrium versus embryonic quality in endometriosis-related infertility. Hum Reprod update 8(1):95–103\nBarnhart K, Dunsmoor-Su R, Coutifaris C (2002) Effect of endometriosis on in vitro fertilization. Fertil Steril 77(6):1148–1155\nFreis A, Dietrich JE, Binder M, Holschbach V, Strowitzki T, Germeyer A (2018) Relative morphokinetics assessed by time-lapse imaging are altered in embryos from patients with endometriosis. Reprod Sci 25(8):1279–1285\nKasapoglu I, Kuspinar G, Saribal S, Turk P, Avcı B, Uncu G (2018) Detrimental effects of endometriosis on oocyte morphology in intracytoplasmic sperm injection cycles: a retrospective cohort study. Gynecol Endocrinol 34(3):206–211\nSanchez AM, Vanni VS, Bartiromo L, Papaleo E, Zilberberg E, Candiani M et al (2017) Is the oocyte quality affected by endometriosis? A review of the literature. J Ovarian Res 10(1):43\nMiller JE, Ahn SH, Monsanto SP, Khalaj K, Koti M, Tayade C (2017) Implications of immune dysfunction on endometriosis associated infertility. Oncotarget 8(4):7138–7147\nTaylor RN, Lebovic DI, Mueller MD (2002) Angiogenic factors in endometriosis. Ann N Y Acad Sci 955:89–100 (discussion 118, 396–406)\nHarada T, Iwabe T, Terakawa N (2001) Role of cytokines in endometriosis. Fertil Steril 76(1):1–10\nSikora J, Mielczarek-Palacz A, Kondera-Anasz Z (2012) Imbalance in cytokines from interleukin-1 family—role in pathogenesis of endometriosis. Am J Reprod Immunol 68(2):138–145\nBersinger NA, von Roten S, Wunder DM, Raio L, Dreher E, Mueller MD (2006) PAPP-A and osteoprotegerin, together with interleukin-8 and RANTES, are elevated in the peritoneal fluid of women with endometriosis. Am J Obstet Gynecol 195(1):103–108\nYoshino O, Osuga Y, Koga K, Hirota Y, Tsutsumi O, Yano T et al (2003) Concentrations of interferon-gamma-induced protein-10 (IP-10), an antiangiogenic substance, are decreased in peritoneal fluid of women with advanced endometriosis. Am J Reprod Immunol 50(1):60–65\nDa Broi MG, Giorgi VSI, Wang F, Keefe DL, Albertini D, Navarro PA (2018) Influence of follicular fluid and cumulus cells on oocyte quality: clinical implications. J Assist Reprod Genet 35(5):735–751\nSarapik A, Velthut A, Haller-Kikkatalo K, Faure GC, Béné MC, de Carvalho Bittencourt M et al (2012) Follicular proinflammatory cytokines and chemokines as markers of IVF success. Clin Dev Immunol. https://doi.org/10.1155/2012/606459\nSingh AK, Dutta M, Chattopadhyay R, Chakravarty B, Chaudhury K (2016) Intrafollicular interleukin-8, interleukin-12, and adrenomedullin are the promising prognostic markers of oocyte and embryo quality in women with endometriosis. J Assist Reprod Genet 33(10):1363–1372\nNikolettos N, Kupker W, Al-Hasani S, Demirel LC, Schöpper B, Sturm R et al (2000) ICSI outcome in patients of 40 years age and over: a retrospective analysis. Eur J Obstet Gynecol Reprod Biol 91(2):177–182\nKollmann Z, Schneider S, Fux M, Bersinger NA, von Wolff M (2017) Gonadotrophin stimulation in IVF alters the immune cell profile in follicular fluid and the cytokine concentrations in follicular fluid and serum. Hum Reprod 32(4):820–831\nPodgaec S, Abrao MS, Dias JA Jr, Rizzo LV, Oliveira RM, Baracat EC (2007) Endometriosis: an inflammatory disease with a Th2 immune response component. Hum Reprod 22(5):1373–1379\nHsu CC, Yang BC, Wu MH, Huang KE (1997) Enhanced interleukin-4 expression in patients with endometriosis. Fertil Steril 67(6):1059–1064\nAntsiferova YS, Sotnikova NY, Posiseeva LV, Shor AL (2005) Changes in the T-helper cytokine profile and in lymphocyte activation at the systemic and local levels in women with endometriosis. Fertil Steril 84(6):1705–1711\nOuYang Z, Hirota Y, Osuga Y, Hamasaki K, Hasegawa A, Tajima T et al (2008) Interleukin-4 stimulates proliferation of endometriotic stromal cells. Am J Pathol 173(2):463–469\nZurawski G, de Vries JE (1994) Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells but not on T cells. Immunol Today 15(1):19–26\nGallinelli A, Ciaccio I, Giannella L, Salvatori M, Marsella T, Volpe A (2003) Correlations between concentrations of interleukin-12 and interleukin-13 and lymphocyte subsets in the follicular fluid of women with and without polycystic ovary syndrome. Fertil Steril 79(6):1365–1372\nBao K, Reinhardt RL (2015) The differential expression of IL-4 and IL-13 and its impact on type-2 immunity. Cytokine 75(1):25–37\nInoue Y, Konieczny BT, Wagener ME, McKenzie AN, Lakkis FG (2001) Failure to induce neonatal tolerance in mice that lack both IL-4 and IL-13 but not in those that lack IL-4 alone. J Immunol 167(2):1125–1128\nChegini N, Roberts M, Ripps B (2003) Differential expression of interleukins (IL)-13 and IL-15 in ectopic and eutopic endometrium of women with endometriosis and normal fertile women. Am J Reprod Immunol 49(2):75–83\nWang XM, Ma ZY, Song N (2018) Inflammatory cytokines IL-6, IL-10, IL-13, TNF-α and peritoneal fluid flora were associated with infertility in patients with endometriosis. Eur Rev Med Pharmacol Sci 22(9):2513–2518\nKasson BG, Gorospe WC (1989) Effects of interleukins 1, 2 and 3 on follicle-stimulating hormone-induced differentiation of rat granulosa cells. Mol Cell Endocrinol 62(1):103–111\nWu MY, Ho HN (2003) The role of cytokines in endometriosis. Am J Reprod Immunol 49(5):285–296\nAhn SH, Edwards AK, Singh SS, Young SL, Lessey BA, Tayade C (2015) IL-17A contributes to the pathogenesis of endometriosis by triggering proinflammatory cytokines and angiogenic growth factors. J Immunol 195(6):2591–2600\nGogacz M, Winkler I, Bojarska-Junak A, Tabarkiewicz J, Semczuk A, Rechberger T et al (2016) Increased percentage of Th17 cells in peritoneal fluid is associated with severity of endometriosis. J Reprod Immunol 117:39–44\nHarrington LE, Mangan PR, Weaver CT (2006) Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 18(3):349–356\nMachelon V, Nome F, Durand-Gasselin I, Emilie D (1995) Macrophage and granulosa interleukin-1 beta mRNA in human ovulatory follicles. Hum Reprod 10(8):2198–2203\nJasper M, Norman RJ (1995) Immunoactive interleukin-1 beta and tumour necrosis factor-alpha in thecal, stromal and granulosa cell cultures from normal and polycystic ovaries. Hum Reprod 10(6):1352–1354\nGérard N, Caillaud M, Martoriati A, Goudet G, Lalmanach AC (2004) The interleukin-1 system and female reproduction. J Endocrinol 180(2):203–212\nZollner KP, Hofmann T, Zollner U (2013) Good fertilization results associated with high IL-1beta concentrations in follicular fluid of IVF patients. J Reprod Med 58(11–12):485–490\nDang X, Zhu Q, He Y, Wang Y, Lu Y, Li X et al (2017) IL-1β Upregulates StAR and progesterone production through the ERK1/2- and p38-mediated CREB signaling pathways in human granulosa-lutein cells. Endocrinology 158(10):3281–3291\nField SL, Dasgupta T, Cummings M, Orsi NM (2014) Cytokines in ovarian folliculogenesis, oocyte maturation and luteinisation. Mol Reprod Dev 81(4):284–314\nUri-Belapolsky S, Miller I, Shaish A, Levi M, Harats D, Ninio-Many L et al (2017) Interleukin 1-alpha deficiency increases the expression of follicle-stimulating hormone receptors in granulosa cells. Mol Reprod Dev 84(6):460–467\nUri-Belapolsky S, Shaish A, Eliyahu E, Grossman H, Levi M, Chuderland D et al (2014) Interleukin-1 deficiency prolongs ovarian lifespan in mice. Proc Natl Acad Sci USA 111(34):12492–12497\nHata H (2005) Bone lesions and macrophage inflammatory protein-1 alpha (MIP-1α) in human multiple myeloma. Leuk Lymphoma 46(7):967–972\nKawano Y, Fukuda J, Nasu K, Nishida M, Narahara H, Miyakawa I (2004) Production of macrophage inflammatory protein-3alpha in human follicular fluid and cultured granulosa cells. Fertil Steril 82(Suppl 3):1206–1211\nAuthor information\nAuthors and Affiliations\nContributions\nXD Mao, CY Hu, MC Zhu and HL Ou performed immunological detection. XD Mao and HL Ou performed the statistical analysis. YL Qian and XD Mao conceived and directed the project. All authors participated in writing the manuscript.\nCorresponding author\nEthics declarations\nConflict of interest\nThe authors have no conflicts of interest to declare.\nAdditional information\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nRights and permissions\nAbout this article\nCite this article\nMao, XD., Hu, CY., Zhu, MC. et al. Immunological microenvironment alterations in follicles of women with proven severe endometriosis undergoing in vitro fertilization. Mol Biol Rep 46, 4675–4684 (2019). https://doi.org/10.1007/s11033-019-04753-3\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s11033-019-04753-3","source_license":"public-domain-us","license_restricted":false}