Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter June 20, 2018

IL-37 affects the occurrence and development of endometriosis by regulating the biological behavior of endometrial stromal cells through multiple signaling pathways

Jianfa Jiang, Kenan Yu, Zhaoying Jiang and Min Xue
From the journal Biological Chemistry

Abstract

Endometriosis (EMs) is a chronic inflammatory condition. Interleukin (IL)-37 is a member of the IL-1 family and an anti-inflammatory cytokine. This study aimed to evaluate the possible role of IL-37 in the EMs pathogenesis. We investigated the in vivo effect of IL-37 on EMs by injection with recombinant human IL-37 (rhIL-37) into EMs mice. Furthermore, we evaluated the in vitro effects of IL-37 on proliferation, adhesion, migration and invasiveness of endometrial stromal cells (ESCs), and explored whether Wnt/β-catenin and mitogen-activated protein kinase (MAPK) pathways were involved in this process. In cultured ESCs, IL-37 overexpression significantly suppressed both protein and mRNA expression of the inflammation-associated cytokines, including IL-1β, IL-6, IL-10 and tumor necrosis factor (TNF-α). Furthermore, IL-37 overexpression significantly inhibited ESCs proliferation, adhesion, migration, invasion and the activity of matrix metalloproteinase (MMP)-2 and MMP-9. In contrast, knockdown of IL-37 exerted the opposite effects. Importantly, the IL-37-mediated action in ESCs was through inactivation of Wnt/β-catenin, p38 MAPK, extracellular signal-related kinases MAPK and c-Jun N-terminal kinase MAPK pathways. Moreover, EMs mice treated with rhIL-37 showed the decreased endometriotic-like lesion size and lesion weight, lower expression of IL-1β, IL-6, IL-10, TNF-α, vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-I (ICAM-I) and MMP-2/9 activity in peritoneal fluid compared with the wide type (WT) EMs mice. These findings suggest that IL-37 suppresses cell proliferation, adhesion, migration and invasion of human ESCs through multiple signaling pathways, thereby affecting the occurrence and development of EMs.

Acknowledgments

The present study was supported by the New Xiangya Talent Project of The Third Xiangya Hospital of Central South University (Grant No. JY201706).

  1. Conflict of interest statement: The authors declare no conflicts of interest.

References

Altan, M., Bruner-Tran, K.L., Osteen, K.G., and Palmer, S. (2008). JNK inhibitor AS-01 causes regression of endometriosis and suppression of inflammatory cytokines and tissue remodeling enzymes. Biol. Reprod. 78, 168–169.10.1093/biolreprod/78.s1.168cSearch in Google Scholar

Ayala Yanez, R. and Mota Gonzalez, M. (2007). Endometriosis: physiopathology and investigation trends (first part). Ginecol. Obstet. Mex. 75, 477–483.Search in Google Scholar

Ballak, D.B., van Diepen, J.A., Moschen, A.R., Jansen, H.J., Hijmans, A., Groenhof, G.J., Leenders, F., Bufler, P., Boekschoten, M.V., Muller, M., et al. (2014). IL-37 protects against obesity-induced inflammation and insulin resistance. Nat. Commun. 5, 4711.10.1038/ncomms5711Search in Google Scholar

Bersinger, N.A., Günthert, A.R., Mckinnon, B., Johann, S., and Mueller, M.D. (2011). Dose-response effect of interleukin (IL)-1β, tumour necrosis factor (TNF)-α, and interferon-γ on the in vitro production of epithelial neutrophil activating peptide-78 (ENA-78), IL-8, and IL-6 by human endometrial stromal cells. Arch. Gynecol. Obstet. 283, 1291–1296.10.1007/s00404-010-1520-3Search in Google Scholar

Beste, M.T., Pfaffle-Doyle, N., Prentice, E.A., Morris, S.N., Lauffenburger, D.A., Isaacson, K.B., and Griffith, L.G. (2014). Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation. Sci. Transl. Med. 6, 222ra216.10.1126/scitranslmed.3007988Search in Google Scholar

Boraschi, D., Lucchesi, D., Hainzl, S., Leitner, M., Maier, E., Mangelberger, D., Oostingh, G.J., Pfaller, T., Pixner, C., and Posselt, G. (2011). IL-37: a new anti-inflammatory cytokine of the IL-1 family. Eur. Cytokine Network 22, 127–147.10.1684/ecn.2011.0288Search in Google Scholar

Bulau, A.M., Nold, M.F., Li, S., Nold-Petry, C.A., Fink, M., Mansell, A., Schwerd, T., Hong, J., Rubartelli, A., Dinarello, C.A., et al. (2014). Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses. Proc. Natl. Acad. Sci. USA 111, 2650–2655.10.1073/pnas.1324140111Search in Google Scholar

Cavalli, G. and Dinarello, C. (2018). Suppression of inflammation and acquired immunity by IL-37. Immunol. Rev. 281, 179–190.10.1111/imr.12605Search in Google Scholar

Chan, R.W.S., Schwab, K.E., and Gargett, C.E. (2004). Clonogenicity of human endometrial epithelial and stromal cells. Biol. Reprod. 70, 1738–1750.10.1095/biolreprod.103.024109Search in Google Scholar

Coll-Miro, M., Francos-Quijorna, I., Santos-Nogueira, E., Torres-Espin, A., Bufler, P., Dinarello, C.A., and Lopez-Vales, R. (2016). Beneficial effects of IL-37 after spinal cord injury in mice. Proc. Natl. Acad. Sci. USA 113, 1411–1416.10.1073/pnas.1523212113Search in Google Scholar

De, Z.D., Borghese, B., and Chapron, C. (2010). Endometriosis and infertility: pathophysiology and management. Lancet 376, 730–738.10.1016/S0140-6736(10)60490-4Search in Google Scholar

Fan, Y.Y., Chen, H.Y., Chen, W., Liu, Y.N., Fu, Y., and Wang, L.N. (2018). Expression of inflammatory cytokines in serum and peritoneal fluid from patients with different stages of endometriosis. Gynecol. Endocrinol. 34, 507–512.10.1080/09513590.2017.1409717Search in Google Scholar

Fortin, M., Lepine, M., Page, M., Osteen, K., Massie, B., Hugo, P., and Steff, A.M. (2003). An improved mouse model for endometriosis allows noninvasive assessment of lesion implantation and development. Fertil. Steril. 80, 832–838.10.1016/S0015-0282(03)00986-5Search in Google Scholar

Geun, Y.S., Sung, W.Y., Yun, L.H., Il, K.Y., Jin-Woo, L., and Choon, P.D. (2013). Increased Expression of pattern recognition receptors and nitric oxide synthase in patients with endometriosis. Int. J. Med. Sci. 10, 1199–1208.10.7150/ijms.5169Search in Google Scholar PubMed PubMed Central

Hever, A., Roth, R.B., Hevezi, P., Marin, M.E., Acosta, J.A., Acosta, H., Rojas, J., Herrera, R., Grigoriadis, D., White, E., et al. (2007). Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator. Proc. Natl. Acad. Sci. USA 104, 12451–12456.10.1073/pnas.0703451104Search in Google Scholar PubMed PubMed Central

Imaeda, H., Takahashi, K., Fujimoto, T., Kasumi, E., Ban, H., Bamba, S., Sonoda, H., Shimizu, T., Fujiyama, Y., and Andoh, A. (2013). Epithelial expression of interleukin-37b in inflammatory bowel disease. Clin. Exp. Immunol. 172, 410–416.10.1111/cei.12061Search in Google Scholar PubMed PubMed Central

Jeung, I., Cheon, K., and Kim, M.R. (2016). Decreased cytotoxicity of peripheral and peritoneal natural killer cell in endometriosis. Biomed. Res. Int. 2016, 2916070.10.1155/2016/2916070Search in Google Scholar PubMed PubMed Central

Jiang, J., Deng, Y., Xue, W., Zheng, T., and Sun, A. (2016). Increased expression of interleukin 37 in the eutopic and ectopic endometrium of patients with ovarian endometriosis. Reprod. Sci. 23, 244–248.10.1177/1933719115602775Search in Google Scholar PubMed

Kaabachi, W., Kacem, O., Belhaj, R., Hamzaoui, A., and Hamzaoui, K. (2017). Interleukin-37 in endometriosis. Immunol. Lett. 185, 52–55.10.1016/j.imlet.2017.03.012Search in Google Scholar PubMed

Kim, H.O., Yang, K.M., Kang, I.S., Koong, M.K., Kim, H.S., Zhang, X., and Kim, I. (2007). Expression of CD44s, vascular endothelial growth factor, matrix metalloproteinase-2 and Ki-67 in peritoneal, rectovaginal and ovarian endometriosis. J. Reprod. Med. 52, 207–213.Search in Google Scholar

Kusakabe, K.T., Abe, H., Kondo, T., Kato, K., Okada, T., and Otsuki, Y. (2010). DNA microarray analysis in a mouse model for endometriosis and validation of candidate factors with human adenomyosis. J. Reprod. Immunol. 85, 149–160.10.1016/j.jri.2010.02.008Search in Google Scholar PubMed

Lee, M.Y., Kim, S.H., Oh, Y.S., Heo, S.H., Kim, K.H., Chae, H.D., Kim, C.H., and Kang, B.M. (2018). Role of interleukin-32 in the pathogenesis of endometriosis: in vitro, human and transgenic mouse data. Hum. Reprod. 33, 807–816.10.1093/humrep/dey055Search in Google Scholar PubMed

Mambelli, L.I., Mattos, R.C., Winter, G.H., Madeiro, D.S., Morais, B.P., Malschitzky, E., Miglino, M.A., Kerkis, A., and Kerkis, I. (2014). Changes in expression pattern of selected endometrial proteins following mesenchymal stem cells infusion in mares with endometrosis. PLoS One 9, e97889.10.1371/journal.pone.0097889Search in Google Scholar PubMed PubMed Central

Matsuzaki, S. and Darcha, C. (2013). Involvement of the Wnt/β-catenin signaling pathway in the cellular and molecular mechanisms of fibrosis in endometriosis. Plos One 8, e76808.10.1371/journal.pone.0076808Search in Google Scholar PubMed PubMed Central

Matsuzaki, S. and Darcha, C. (2015). Co-operation between the AKT and ERK signaling pathways may support growth of deep endometriosis in a fibrotic microenvironment in vitro. Hum. Reprod. 30, 1606–1616.10.1093/humrep/dev108Search in Google Scholar PubMed

McNamee, E.N., Masterson, J.C., Jedlicka, P., McManus, M., Grenz, A., Collins, C.B., Nold, M.F., Nold-Petry, C., Bufler, P., Dinarello, C.A., et al. (2011). Interleukin 37 expression protects mice from colitis. Proc. Natl. Acad. Sci. USA 108, 16711–16716.10.1073/pnas.1111982108Search in Google Scholar PubMed PubMed Central

Moretti, S., Bozza, S., Oikonomou, V., Renga, G., Casagrande, A., Iannitti, R.G., Puccetti, M., Garlanda, C., Kim, S., Li, S., et al. (2014). IL-37 inhibits inflammasome activation and disease severity in murine aspergillosis. PLoS Pathog. 10, e1004462.10.1371/journal.ppat.1004462Search in Google Scholar PubMed PubMed Central

Mott, J.D. and Werb, Z. (2004). Regulation of matrix biology by matrix metalloproteinases. Curr. Opin. Cell Biol. 16, 558–564.10.1016/j.ceb.2004.07.010Search in Google Scholar PubMed PubMed Central

Nold, M.F., Nold-Petry, C.A., Zepp, J.A., Palmer, B.E., Bufler, P., and Dinarello, C.A. (2010). IL-37 is a fundamental inhibitor of innate immunity. Nat. Immunol. 11, 1014–1022.10.1038/ni.1944Search in Google Scholar PubMed PubMed Central

Novella-Maestre, E., Carda, C., Noguera, I., Ruiz-Sauri, A., Garcia-Velasco, J.A., Simon, C., and Pellicer, A. (2009). Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis. Hum. Reprod. 24, 1025–1035.10.1093/humrep/den499Search in Google Scholar PubMed

Schulke, L., Berbic, M., Manconi, F., Tokushige, N., Markham, R., and Fraser, I.S. (2009). Dendritic cell populations in the eutopic and ectopic endometrium of women with endometriosis. Hum. Reprod. 24, 1695–1703.10.1093/humrep/dep071Search in Google Scholar PubMed

Wang, S., An, W., Yao, Y., Chen, R., Zheng, X., Yang, W., Zhao, Y., Hu, X., Jiang, E., Bie, Y., et al. (2015). Interleukin 37 expression inhibits STAT3 to suppress the proliferation and invasion of human cervical cancer cells. J. Cancer 6, 962–969.10.7150/jca.12266Search in Google Scholar PubMed PubMed Central

Wu, W., Wang, W., Wang, Y., Li, W., Yu, G., Li, Z., Fang, C., Shen, Y., Sun, Z., Han, L., et al. (2015). IL-37b suppresses T cell priming by modulating dendritic cell maturation and cytokine production via dampening ERK/NF-kappaB/S6K signalings. Acta Biochim. Biophys. Sin. (Shanghai) 47, 597–603.10.1093/abbs/gmv058Search in Google Scholar PubMed

Yoshino, O., Osuga, Y., Hirota, Y., Koga, K., Hirata, T., Harada, M., Morimoto, C., Yano, T., Nishii, O., and Tsutsumi, O. (2004). Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis. Am. J. Reprod. Immunol. 52, 306.10.1111/j.1600-0897.2004.00231.xSearch in Google Scholar PubMed

Zhou, W.D., Yang, H.M., Wang, Q., Su, D.Y., Liu, F.A., Zhao, M., Chen, Q.H., and Chen, Q.X. (2010). SB203580, a p38 mitogen-activated protein kinase inhibitor, suppresses the development of endometriosis by down-regulating proinflammatory cytokines and proteolytic factors in a mouse model. Hum. Reprod. 25, 3110–3116.10.1093/humrep/deq287Search in Google Scholar PubMed

Received: 2018-05-16
Accepted: 2018-06-13
Published Online: 2018-06-20
Published in Print: 2018-10-25

©2018 Walter de Gruyter GmbH, Berlin/Boston