Skip to main content

Advertisement

SpringerLink
Log in

Upregulation of Interleukin 35 in Patients With Endometriosis Stimulates Cell Proliferation

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

In this study, we investigated the expression of interleukin 35 (IL-35) and its receptors in endometriosis, analyzed the function of IL-35 in primary culture model of endometrial stromal cells (ESCs), and evaluated their clinicapathological significance. Peripheral blood (PB) and peritoneal fluid (PF) were collected from 37 women with endometriosis and 24 control women. The ectopic endometrium was obtained from patients with endometriosis undergoing laparoscopic surgery. The eutopic and normal endometrium were collected by endometrial biopsy. Levels of IL-35 in PB and PF were evaluated by enzyme-linked immunosorbent assay. Women with endometriosis had higher levels of IL-35 compared to controls both in PB and in PF. Levels of n IL-35 were increased in patients with advanced stage endometriosis compared to those with early stages in PF. A significant upregulation of IL-35 was observed in patients with ovarian endometriosis accompanied with pelvic implants (PI) compared to those without PI in PB and PF. The relative messenger RNA and protein expression of EBi3 and p35, the subunits of IL-35, were significantly higher in ectopic endometrium than in eutopic and healthy endometrium as measured by immunohistochemistry and quantitative polymerase chain reaction. The ESCs from endometriosis displayed a remarkable overexpression of IL-35 receptor subunits, ILl2Rp2 and gp130, compared to those from controls. Moreover, recombined human IL-35 protein stimulated the upregulation of ILl2Rβ2 and gp130 and facilitated proliferation of ESCs. Our study provides the first evidence that IL-35 was involved in the pathogenesis of endometriosis through suppressing immunoreaction and promoting proliferation of ESCs. IL-35 may potentially serve as a biomarker for endometriosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799.

    PubMed  Google Scholar 

  2. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3): 511–519.

    Article  CAS  PubMed  Google Scholar 

  3. Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3(2): 93–110.43.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Dmowski WP, Steele RW, Baker GF. Deficient cellular immunity in endometriosis. Am J Obstet Gynecol. 1981;141(4): 377–383.

    Article  CAS  PubMed  Google Scholar 

  5. Eisenberg VH, Zolti M, Soriano D. Is there an association between autoimmunity and endometriosis? Autoimmun Rev. 2012;11(11): 806–814.

    Article  CAS  PubMed  Google Scholar 

  6. Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endo-metriosis. Fertil Steril. 2001;75(1): 1–10.

    Article  CAS  PubMed  Google Scholar 

  7. Berbic M, Fraser IS. Regulatory T cells and other leukocytes in the pathogenesis of endometriosis. J Reprod Immunol. 2011;88(2): 149–155.

    Article  CAS  PubMed  Google Scholar 

  8. Berbic M, Hey-Cunningham AJ, Ng C, et al. The role of Foxp3+ regulatory T-cells in endometriosis: A potential controlling mechanism for a complex, chronic immunological condition. Hum Reprod. 2010;25(4): 900–907.

    Article  CAS  PubMed  Google Scholar 

  9. Olkowska-Truchanowicz J, Bocian K, Maksym RB, et al. CD4+CD25+ FOXP3+regulatory T cells in peripheral blood and peritoneal fluid of patients with endometriosis. Hum Reprod. 2013;28(1): 119–124.

    Article  CAS  PubMed  Google Scholar 

  10. Podgaec S, Rizzo LV, Fernandes LF, Baracat EC, Abrao MS. CD4(+) CD25(high) Foxp3(+) cells increased in the peritoneal fluid ofpatients with endometriosis. Am JReprod Immunol. 2012;68(4): 301–308.

    Article  CAS  Google Scholar 

  11. Li MQ, Wang Y, Chang KK, et al. CD4+Foxp3+ regulatory T cell differentiation mediated by endometrial stromal cell-derived TECK promotes the growth and invasion of endometriotic lesions. Cell Death Dis. 2014;5: e1436.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Suen JL, Chang Y, Chiu PR, et al. Serum level of IL-10 is increased in patients with endometriosis, and IL-10 promotes the growth of lesions in a murine model. Am J Pathol. 2014;184(2): 464–471.

    Article  CAS  PubMed  Google Scholar 

  13. Tagashira Y, Taniguchi F, Harada T, Ikeda A, Watanabe A, Terakawa N. Interleukin-10 attenuates TNF-alpha-induced interleukin-6 production in endometriotic stromal cells. Fertil Steril. 2009;91(suppl 5): 2185–2192.

    Article  Google Scholar 

  14. Omwandho CO, Konrad L, Halis G, Oehmke F, Tinneberg HR. Role of TGF-beta in normal human endometrium and endometriosis. Hum Reprod. 2010;25(1): 101–109.

    Article  CAS  PubMed  Google Scholar 

  15. Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169): 566–569.

    Article  CAS  PubMed  Google Scholar 

  16. Niedbala W, Wei XQ, Cai B, et al. IL-35 is a novel cytokine with therapeutic effects against collageninduced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol. 2007;37(11): 3021–3029.

    Article  CAS  PubMed  Google Scholar 

  17. Collison LW, Chaturvedi V, Henderson AL, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010;11(12): 1093–1101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chaturvedi V, Collison LW, Guy CS, Workman CJ, Vignali DA. Cutting edge: human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J Immunol. 2011;186(12): 6661–6666.

    Article  CAS  PubMed  Google Scholar 

  19. Wang Z, Liu JQ, Liu Z, et al. Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis. J Immunol. 2013;190(5): 2415–2423.

    Article  CAS  PubMed  Google Scholar 

  20. Collison LW, Delgoffe GM, Guy CS, et al. The composition and signaling of the IL-35 receptor are unconventional. Nat Immunol. 2012;13(3): 290–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5): 817–821.

    Article  Google Scholar 

  22. Budwit-Novotny DA, McCarty KS, Cox EB, et al. Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res. 1986;46(10): 5419–5425.

    CAS  PubMed  Google Scholar 

  23. OuYang Z, Hirota Y, Osuga Y, et al. Interleukin-4 stimulates proliferation of endometriotic stromal cells. Am J Pathol. 2008;173(2): 463–469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Signorile PG, Baldi A. Serum biomarker for diagnosis of endometriosis. J Cell Physiol. 2014;229(11): 1731–1735.

    Article  CAS  PubMed  Google Scholar 

  25. Schulke L, Berbic M, Manconi F, Tokushige N, Markham R, Fraser IS. Dendritic cell populations in the eutopic and ectopic endometrium of women with endometriosis. Hum Reprod. 2009;24(7): 1695–1703.

    Article  CAS  PubMed  Google Scholar 

  26. Oosterlynck DJ, Meuleman C, Waer M, Vandeputte M, Koninckx PR. The natural killer activity of peritoneal fluid lymphocytes is decreased in women with endometriosis. Fertil Steril. 1992;58(2): 290–295.

    Article  CAS  PubMed  Google Scholar 

  27. Jeung I, Cheon K, Kim MR. Decreased cytotoxicity of peripheral and peritoneal natural killer cell in endometriosis. Biomed Res Int. 2016;2016: 2916070.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wang RX, Yu CR, Dambuza IM, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014;20(6): 633–641.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Nakano S, Morimoto S, Suzuki S, et al. Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis. Rheumatology (Oxford). 2015;54(8): 1498–1506.

    Article  Google Scholar 

  30. Tao Q, Pan Y, Wang Y, et al. Regulatory T cells-derived IL-35 promotes the growth of adult acute myeloid leukemia blasts. Int J Cancer. 2015;137(10): 2384–2393.

    Article  CAS  PubMed  Google Scholar 

  31. Whitehead GS, Wilson RH, Nakano K, Burch LH, Nakano H, Cook DN. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol. 2012;129(1): 207-15e1-5.

    Article  CAS  PubMed  Google Scholar 

  32. Nicholl MB, Ledgewood CL, Chen X, et al. IL-35 promotes pancreas cancer growth through enhancement of proliferation and inhibition of apoptosis: evidence for a role as an autocrine growth factor. Cytokine. 2014;70(2): 126–133.

    Article  CAS  PubMed  Google Scholar 

  33. Zeng JC, Zhang Z, Li TY, et al. Assessing the role of IL-35 in colorectal cancer progression and prognosis. Int J Clin Exp Pathol. 2013;6(9): 1806–1816.

    PubMed  PubMed Central  Google Scholar 

  34. Zhang X, Xu H, Lin J, Qian Y, Deng L. Peritoneal fluid concentrations of interleukin-17 correlate with the severity of endometriosis and infertility of this disorder. BJOG. 2005;112(8): 1153–1155.

    Article  PubMed  Google Scholar 

  35. Gogacz M, Winkler I, Bojarska-Junak A, et al. Increased percentage of Th17 cells in peritoneal fluid is associated with severity of endometriosis. J Reprod Immunol. 2016;117: 39–44.

    Article  CAS  PubMed  Google Scholar 

  36. Tosti C, Pinzauti S, Santulli P, Chapron C, Petraglia F. Pathogenetic mechanisms of deep infiltrating endometriosis. Reprod Sci. 2015;22(9): 1053–1059.

    Article  CAS  PubMed  Google Scholar 

  37. Khan KN, Kitajima M, Fujishita A, et al. Pelvic pain in women with ovarian endometrioma is mostly associated with coexisting peritoneal lesions. Hum Reprod. 2013;28(1): 109–118.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department ofObstetrics and Gynecology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China, 410008

    Chun Zhang MD, Zheng Peng MD, DeYing Ban MD & Yi Zhang MD

Authors
  1. Chun Zhang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zheng Peng MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. DeYing Ban MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Zhang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi Zhang MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, C., Peng, Z., Ban, D. et al. Upregulation of Interleukin 35 in Patients With Endometriosis Stimulates Cell Proliferation. Reprod. Sci. 25, 443–451 (2018). https://doi.org/10.1177/1933719117715123

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719117715123

Keywords

Search

Navigation