Abstract
Objective
Endometriosis is a chronic inflammatory disorder characterized by ectopic growth of endometrial-like tissue. Cytokines play pivotal roles in coordinating tissue inflammation and immune responses. Therefore, some pro- and anti-inflammatory cytokines may be involved or altered in endometriosis were assessed in this study.
Methods
The expression levels of the reference gene ribosomal protein lateral stalk subunit P (RPLP) and interest genes, including interleukin 17 (IL-17), IL-23, IL-25, vascular endothelial growth factor (VEGF), and forkhead box P3 (FoxP3), were measured in the endometriotic tissues of 25 individuals with endometriosis and in the endometrial tissues of 25 control individuals. The cDNA was synthesized from the extracted RNAs, and these expression levels were analyzed using Real-time PCR.
Results
VEGF and FoxP3 were not expressed in endometriotic tissues, while non-endometriotic tissues in control group showed significant levels (VEGF: 4.41 × 10³±1.38 × 10³, FoxP3: 12.3 × 10³±4.18 × 10³; both P = 0.001). IL-17, IL-23, and IL-25 were not detected in either group. The RPLP was only expressed, indicating the presence of some viable active cells in this tissue, which was significantly lower than in controls (P = 0.001). The undetectable level of VEGF in endometriosis suggests that there was no active angiogenesis.
Conclusion
Accordingly, in endometriosis tissue, lymphocytes might be absent or not play a significant role, but the expression of the structural RPLP indicates the presence of some viable, active cells in this tissue. The roles of the immune system and angiogenesis are multidimensional, involved in different stages, from inflammation to immune tolerance. This underscores the importance of other growth factors, which require careful assessment and individualized treatment strategies to address each patient’s specific needs.
Similar content being viewed by others
Data availability
The author confirms that all necessary data analyzed during this study are included in this article. The more information or additional data are, available from the authors upon reasonable request.
References
Mahmood TA, Templeton A (1991) Prevalence and genesis of endometriosis. Hum Reprod 6:544–549. https://doi.org/10.1093/oxfordjournals.humrep.a137377
Foti PV, Farina R, Palmucci S et al (2018) Endometriosis: clinical features, MR imaging findings and pathologic correlation. Insights Imaging 9:149–172. https://doi.org/10.1007/s13244-017-0591-0
Bazot M, Bharwani N, Huchon C et al (2017) European society of urogenital radiology (ESUR) guidelines: MR imaging of pelvic endometriosis. Eur Radiol 27:2765–2775. https://doi.org/10.1007/s00330-016-4673-z
Coutinho A Jr., Bittencourt LK, Pires CE et al (2011) MR imaging in deep pelvic endometriosis: a pictorial essay. Radiographics 31:549–567. https://doi.org/10.1148/rg.312105144
Chamie LP, Blasbalg R, Pereira RM, Warmbrand G, Serafini PC (2011) Findings of pelvic endometriosis at transvaginal US, MR imaging, and laparoscopy. Radiographics 31:E77–100. https://doi.org/10.1148/rg.314105193
Patel BG, Lenk EE, Lebovic DI, Shu Y, Yu J, Taylor RN (2018) Pathogenesis of endometriosis: interaction between endocrine and inflammatory pathways. Best Pract Res Clin Obstet Gynaecol 50:50–60. https://doi.org/10.1016/j.bpobgyn.2018.01.006
Sampson JA (1921) Perforating hemorrhagic (Chocolate) cysts of the ovary. Arch Surg 3:245–323. https://doi.org/10.1001/archsurg.1921.01110080003001
Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM (1984) Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol 64:151–154
Lamceva J, Uljanovs R, Strumfa I (2023) The main theories on the pathogenesis of endometriosis. Int J Mol Sci 24. https://doi.org/10.3390/ijms24054254
Wenzl R, Kiesel L, Huber JC, Wieser F (2003) Endometriosis: a genetic disease. Drugs Today (Barc) 39:961–972. https://doi.org/10.1358/dot.2003.39.12.799414
Privitera G, O’Brien K, Misajon R, Lin CY (2023) Endometriosis Symptomatology, Dyspareunia, and Sexual Distress Are Related to Avoidance of Sex and Negative Impacts on the Sex Lives of Women with Endometriosis. Int J Environ Res Public Health 20. https://doi.org/10.3390/ijerph20043362
Greygoose E, Metharom P, Kula H et al (2025) The Estrogen-Immune interface in endometriosis. Cells 14. https://doi.org/10.3390/cells14010058
Crispim PCA, Jammal MP, Antao PKA et al (2020) IL6, IL8, and IL10 in the distinction of malignant ovarian neoplasms and endometriomas. Am J Reprod Immunol 84:e13309. https://doi.org/10.1111/aji.13309
Burney RO, Giudice LC (2012) Pathogenesis and pathophysiology of endometriosis. Fertil Steril 98:511–519. https://doi.org/10.1016/j.fertnstert.2012.06.029
Oala IE, Mitranovici MI, Chiorean DM et al (2024) Endometriosis and the role of Pro-Inflammatory and Anti-Inflammatory cytokines in pathophysiology: A narrative review of the literature. Diagnostics (Basel) 14. https://doi.org/10.3390/diagnostics14030312
Vallve-Juanico J, Houshdaran S, Giudice LC (2019) The endometrial immune environment of women with endometriosis. Hum Reprod Update 25:564–591. https://doi.org/10.1093/humupd/dmz018
Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R, Tayade C (2015) Pathophysiology and Immune Dysfunction in Endometriosis. Biomed Res Int 2015, 795976 https://doi.org/10.1155/2015/795976
Takebayashi A, Kimura F, Kishi Y et al (2015) Subpopulations of macrophages within eutopic endometrium of endometriosis patients. Am J Reprod Immunol 73:221–231
Mortlock S, McKinnon B, Montgomery GW (2021) Genetic regulation of transcription in the endometrium in health and disease. Front Reprod Health 3:795464. https://doi.org/10.3389/frph.2021.795464
Shigesi N, Harris HR, Fang H et al (2025) The phenotypic and genetic association between endometriosis and immunological diseases. Hum Reprod 40:1195–1209. https://doi.org/10.1093/humrep/deaf062
Zhou WJ, Yang HL, Shao J et al (2019) Anti-inflammatory cytokines in endometriosis. Cell Mol Life Sci 76:2111–2132. https://doi.org/10.1007/s00018-019-03056-x
Krygere L, Jukna P, Jariene K, Drejeriene E (2024) Diagnostic potential of cytokine biomarkers in endometriosis: challenges and insights. Biomedicines 12:2867. https://doi.org/10.3390/biomedicines12122867
Tarokh M, Ghaffari Novin M, Poordast T et al (2019) Serum and peritoneal fluid cytokine profiles in infertile women with endometriosis. Iran J Immunol 16:151–162. https://doi.org/10.22034/IJI.2019.80258
Andreoli CG, Genro VK, Souza CA et al (2011) T helper (Th)1, Th2, and Th17 Interleukin pathways in infertile patients with minimal/mild endometriosis. Fertil Steril 95:2477–2480. https://doi.org/10.1016/j.fertnstert.2011.02.019
Sikora J, Smycz-Kubanska M, Mielczarek-Palacz A, Bednarek I, Kondera-Anasz Z (2018) The involvement of multifunctional TGF-beta and related cytokines in pathogenesis of endometriosis. Immunol Lett 201:31–37. https://doi.org/10.1016/j.imlet.2018.10.011
Bungum HF, Nygaard U, Vestergaard C, Martensen PM, Knudsen UB (2016) Increased IL-25 levels in the peritoneal fluid of patients with endometriosis. J Reprod Immunol 114:6–9. https://doi.org/10.1016/j.jri.2016.01.003
Miller JE, Ahn SH, Marks RM et al (2020) IL-17A modulates peritoneal macrophage recruitment and M2 polarization in endometriosis. Front Immunol 11:108. https://doi.org/10.3389/fimmu.2020.00108
Delbandi AA, Mahmoudi M, Shervin A, Farhangnia P, Mohammadi T, Zarnani AH (2025) Increased Circulating T helper 17 (T(H)17) cells and endometrial tissue IL-17-producing cells in patients with endometriosis compared with non-endometriotic subjects. Reprod Biol 25:101019. https://doi.org/10.1016/j.repbio.2025.101019
Shi JL, Zheng ZM, Chen M, Shen HH, Li MQ, Shao J (2022) IL-17: an important pathogenic factor in endometriosis. Int J Med Sci 19:769–778. https://doi.org/10.7150/ijms.71972
Sobstyl M, Mertowska P, Mertowski S et al (2024) The PD-1/PD-L1 gateway: peripheral immune regulation in the pathogenesis of endometriosis. Int J Mol Sci 25:6775. https://doi.org/10.3390/ijms25126775
Gonzalez-Canto E, Mari-Alexandre J, Gilabert-Estelles J (2022) Exploring the feasibility of anti-PD-1/PD-L1 immunotherapy in endometriosis-associated ovarian cancer. Fertil Steril 117:169–170. https://doi.org/10.1016/j.fertnstert.2021.11.007
Sisnett DJ, Zutautas KB, Miller JE et al (2024) The dysregulated IL-23/TH17 Axis in endometriosis pathophysiology. J Immunol 212:1428–1441. https://doi.org/10.4049/jimmunol.2400018
Ahn 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 195:2591–2600. https://doi.org/10.4049/jimmunol.1501138
Kang YJ, Cho HJ, Lee Y et al (2023) IL-17A and Th17 Cells Contribute to Endometrial Cell Survival by Inhibiting Apoptosis and NK Cell Mediated Cytotoxicity of Endometrial Cells via ERK1/2 Pathway. Immune Netw 23, e14 https://doi.org/10.4110/in.2023.23.e14
Castle RD (2024) IL-6 signaling pathway differentiation for endometriosis and inflammatory diseases. Explor Immunol 4:476–489
Gilabert-Estelles J, Castello R, Gilabert J et al (2005) Plasminogen activators and plasminogen activator inhibitors in endometriosis. Front Biosci 10:1162–1176. https://doi.org/10.2741/1609
Imudia AN, Kumar S, Saed GM, Diamond MP (2008) Pathogenesis of Intra-abdominal and pelvic adhesion development. Semin Reprod Med 26:289–297. https://doi.org/10.1055/s-0028-1082387
Chung MS, Han SJ (2022) Endometriosis-Associated angiogenesis and Anti-angiogenic therapy for endometriosis. Front Glob Womens Health 3:856316. https://doi.org/10.3389/fgwh.2022.856316
Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M (1998) Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod 13:1686–1690. https://doi.org/10.1093/humrep/13.6.1686
Bourlev V, Volkov N, Pavlovitch S, Lets N, Larsson A, Olovsson M (2006) The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions. Reproduction 132:501–509
do Rêgo ACM, Araújo-Filho I (2025) Immunopathology and therapeutic perspectives of endometriosis: scientific gaps and emerging advances in translational immunotherapy. Int J Innovative Res Med Sci (IJIRMS) 10
Knez J, Kovacic B, Goropevsek A (2024) The role of regulatory T-cells in the development of endometriosis. Hum Reprod. https://doi.org/10.1093/humrep/deae103
Acknowledgements
The authors wish to thank the vice-chancellor of deputy research for financial support (grant number 4002019) and the patients participating in this study.
Funding
This work was supported by the Mashhad University of Medical Sciences, Iran [Grant number: 4002019].
Author information
Authors and Affiliations
Contributions
Data analysis, reviewing and finalizing the manuscript: L.H and M.J; Doing experiments. S.A.G and S. A.P: manuscript drafting and analyzing Data: S.G: research director, conception and design of the study. All authors have read and approved the final manuscript.
Corresponding author
Ethics declarations
Declarations
We have not used any AI tools or technologies to prepare this manuscript.
Ethics approval and consent to participate
All procedures involving human participants complied with ethical standards set by the institutional and national research committees, as well as the 1964 Helsinki declaration and its revisions. This study received approval from the Research Ethics Committee of Mashhad University of Medical Sciences (IR.MUMS.MEDICAL.REC.1401.503), and informed consent was obtained from all participants.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Hafizi, L., Jafari, M., Ahmadi Ghezeldasht, S. et al. Insights into inflammatory gene expression in endometriosis: a comparative evaluation of tissue biopsy samples. Mol Biol Rep 52, 753 (2025). https://doi.org/10.1007/s11033-025-10856-x
Received:
Accepted:
Published:
Version of record:
DOI: https://doi.org/10.1007/s11033-025-10856-x