IL-37 affects the occurrence and development of endometriosis by regulating the biological behavior of endometrial stromal cells through multiple signaling pathways
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).
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.s1.168cSuche in Google Scholar
Ayala Yanez, R. and Mota Gonzalez, M. (2007). Endometriosis: physiopathology and investigation trends (first part). Ginecol. Obstet. Mex. 75, 477–483.Suche 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/ncomms5711Suche 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/s00404-010-1520-3Suche 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.3007988Suche 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.2011.0288Suche 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.1324140111Suche 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.12605Suche 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.103.024109Suche 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.1523212113Suche 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)60490-4Suche 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, 507–512.10.1080/09513590.2017.1409717Suche 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)00986-5Suche 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.5169Suche 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.0703451104Suche 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.12061Suche 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, 2916070.10.1155/2016/2916070Suche 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, 244–248.10.1177/1933719115602775Suche 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.2017.03.012Suche 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.Suche 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.2010.02.008Suche 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/dey055Suche 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.0097889Suche 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.0076808Suche 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/dev108Suche 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.1111982108Suche 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.1004462Suche 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.2004.07.010Suche 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.1944Suche 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/den499Suche 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/dep071Suche 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.12266Suche 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/gmv058Suche 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.xSuche 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/deq287Suche in Google Scholar PubMed
©2018 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Reviews
- Interaction of volatile organic compounds and underlying liver disease: a new paradigm for risk
- Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I)
- Modifications in small nuclear RNAs and their roles in spliceosome assembly and function
- Minireview
- Transcriptional regulation of human defense peptides: a new direction in infection control
- Research Articles/Short Communications
- Cell Biology and Signaling
- Down-regulated paxillin suppresses cell proliferation and invasion by inhibiting M2 macrophage polarization in colon cancer
- p21Waf1 deficiency does not decrease DNA repair in E1A+cHa-Ras transformed cells by HDI sodium butyrate
- MAC30 knockdown involved in the activation of the Hippo signaling pathway in breast cancer cells
- Inhibition of JAK2/STAT3 signaling suppresses bone marrow stromal cells proliferation and osteogenic differentiation, and impairs bone defect healing
- IL-37 affects the occurrence and development of endometriosis by regulating the biological behavior of endometrial stromal cells through multiple signaling pathways
- Resveratrol alleviates early brain injury following subarachnoid hemorrhage: possible involvement of the AMPK/SIRT1/autophagy signaling pathway
Artikel in diesem Heft
- Frontmatter
- Reviews
- Interaction of volatile organic compounds and underlying liver disease: a new paradigm for risk
- Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I)
- Modifications in small nuclear RNAs and their roles in spliceosome assembly and function
- Minireview
- Transcriptional regulation of human defense peptides: a new direction in infection control
- Research Articles/Short Communications
- Cell Biology and Signaling
- Down-regulated paxillin suppresses cell proliferation and invasion by inhibiting M2 macrophage polarization in colon cancer
- p21Waf1 deficiency does not decrease DNA repair in E1A+cHa-Ras transformed cells by HDI sodium butyrate
- MAC30 knockdown involved in the activation of the Hippo signaling pathway in breast cancer cells
- Inhibition of JAK2/STAT3 signaling suppresses bone marrow stromal cells proliferation and osteogenic differentiation, and impairs bone defect healing
- IL-37 affects the occurrence and development of endometriosis by regulating the biological behavior of endometrial stromal cells through multiple signaling pathways
- Resveratrol alleviates early brain injury following subarachnoid hemorrhage: possible involvement of the AMPK/SIRT1/autophagy signaling pathway