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
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Immune status including the immune cells and cytokine profiles has been implicated in the development of endometriosis. In this study, we analyzed Th17 cells and IL-17A in peritoneal fluid (PF) and endometrial tissues of patients with (n=10) and without (n=26) endometriosis. Our study has shown increased Th17 cell population and IL-17A level in PF with endometriosis patients. To determine the roles of IL-17A and Th17 cells in the development of endometriosis, the effect of IL-17A, major cytokine of Th17, on endometrial cells isolated from endometriotic tissues was examined. Recombinant IL-17A promoted survival of endometrial cells accompanied by increased expression of anti-apoptotic genes, including Bcl-2 and MCL1, and the activation of ERK1/2 signaling. In addition, treatment of IL-17A to endometrial cells inhibited NK cell mediated cytotoxicity and induced HLA-G expression on endometrial cells. IL-17A also promoted migration of endometrial cells. Our data suggest that Th17 cells and IL-17A play critical roles in the development of endometriosis by promoting endometrial cell survival and conferring a resistance to NK cell cytotoxicity through the activation of ERK1/2 signaling. Targeting IL-17A has potential as a new strategy for the treatment of endometriosis.
Abstract
Immune status including the immune cells and cytokine profiles has been implicated in the development of endometriosis. In this study, we analyzed Th17 cells and IL-17A in peritoneal fluid (PF) and endometrial tissues of patients with (n=10) and without (n=26) endometriosis. Our study has shown increased Th17 cell population and IL-17A level in PF with endometriosis patients. To determine the roles of IL-17A and Th17 cells in the development of endometriosis, the effect of IL-17A, major cytokine of Th17, on endometrial cells isolated from endometriotic tissues was examined. Recombinant IL-17A promoted survival of endometrial cells accompanied by increased expression of anti-apoptotic genes, including Bcl-2 and MCL1, and the activation of ERK1/2 signaling. In addition, treatment of IL-17A to endometrial cells inhibited NK cell mediated cytotoxicity and induced HLA-G expression on endometrial cells. IL-17A also promoted migration of endometrial cells. Our data suggest that Th17 cells and IL-17A play critical roles in the development of endometriosis by promoting endometrial cell survival and conferring a resistance to NK cell cytotoxicity through the activation of ERK1/2 signaling. Targeting IL-17A has potential as a new strategy for the treatment of endometriosis.
참고문헌 (37)
- Bulun SE, "Steroidogenic factor-1 and endometriosis", Mol Cell Endocrinol, 300, pp.104~108 (2009)
- Ho HN, "Peritoneal cellular immunity and endometriosis", Am J Reprod Immunol, 38, pp.400~412 (1997)
- Kyama CM, "Potential involvement of the immune system in the development of endometriosis", Reprod Biol Endocrinol, 1, pp.123~ (2003)
- Berbic M, "Regulatory T cells and other leukocytes in the pathogenesis of endometriosis", J Reprod Immunol, 88, pp.149~155 (2011)
- Osuga Y, "Lymphocytes in endometriosis", Am J Reprod Immunol, 65, pp.1~10 (2011)
- D’Hooghe TM, "Endometriosis and subfertility : Is the relationship resolved?", Semin Reprod Med, 21, pp.243~254 (2003)
- Khan KN, "Immunopathogenesis of pelvic endometriosis : role of hepatocyte growth factor, macrophages and ovarian steroids", Am J Reprod Immunol, 60, pp.383~404 (2008)
- Weaver CT, "Th17 : an effector CD4 T cell lineage with regulatory T cell ties", Immunity, 24, pp.677~688 (2006)
- Miossec P, "Interleukin-17 and type 17 helper T cells", N Engl J Med, 361, pp.888~898 (2009)
- Wilke CM, "Deciphering the role of Th17 cells in human disease", Trends Immunol, 32, pp.603~611 (2011)
- Qi W, "Correlation between Th17 cells and tumor microenvironment", Cell Immunol, 285, pp.18~22 (2013)
- Kryczek I, "IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer", J Immunol, 186, pp.4388~4395 (2011)
- Chung Y, "Critical regulation of early Th17 cell differentiation by interleukin-1 signaling", Immunity, 30, pp.576~587 (2009)
- Zhang X, "Peritoneal fluid concentrations of interleukin-17 correlate with the severity of endometriosis and infertility of this disorder", BJOG, 112, pp.1153~1155 (2005)
- Hirata T, "Interleukin(IL)-17A stimulates IL-8 secretion, cyclooxygensase-2 expression, and cell proliferation of endometriotic stromal cells", Endocrinology, 149, pp.1260~1267 (2008)
- Velasco I, "Interleukin-6 and other soluble factors in peritoneal fluid and endometriomas and their relation to pain and aromatase expression", J Reprod Immunol, 84, pp.199~205 (2010)
- Ahn SH, "IL-17A contributes to the pathogenesis of endometriosis by triggering proinflammatory cytokines and angiogenic growth factors", J Immunol, 195, pp.2591~2600 (2015)
- Hirota Y, "Activation of protease-activated receptor 2 stimulates proliferation and interleukin(IL)-6 and IL-8 secretion of endometriotic stromal cells", Hum Reprod, 20, pp.3547~3553 (2005)
- Hirota Y, "Possible involvement of thrombin", protease-activated receptor 1 system in the pathogenesis of endometriosis, 2005, pp.90, 3673~3679
- Park A, "Prostaglandin E2 secreted by thyroid cancer cells contributes to immune escape through the suppression of natural killer(NK)cell cytotoxicity and NK cell differentiation", Front Immunol, 9, pp.1859~ (2018)
- Kang YJ, "An increased level of IL-6 suppresses NK cell activity in peritoneal fluid of patients with endometriosis via regulation of SHP-2 expression", Hum Reprod, 29, pp.2176~2189 (2014)
- Kryczek I, "Cutting edge : opposite effects of IL-1 and IL-2 on the regulation of IL-17+ T cell pool IL-1 subverts IL-2-mediated suppression", J Immunol, 179, pp.1423~1426 (2007)
- Kryczek I, "Endogenous IL-17 contributes to reduced tumor growth and metastasis", Blood, 114, pp.357~359 (2009)
- Gu FM, "IL-17 induces AKT-dependent IL-6", JAK2, Mol Cancer, pp.2011, 10[DOI]
- Grivennikov SI, "Adenoma-linked barrier defects and microbial products drive IL-23", IL-17-mediated tumour growth, 2012, pp.491, 254~258
- Kinugasa T, "Claudins regulate the intestinal barrier in response to immune mediators", Gastroenterology, 118, pp.1001~1011 (2000)
- Li Q, "IL-17 promoted metastasis of non-small-cell lung cancer cells", Immunol Lett, 148, pp.144~150 (2012)
- Kalluri R, "EMT : when epithelial cells decide to become mesenchymal-like cells", J Clin Invest, 119, pp.1417~1419 (2009)
- Au HK, "TGF-βI regulates cell migration through pluripotent transcription factor OCT4 in endometriosis", PLoS One, 10, pp.e0145256~ (2015)
- Wieser F, "Tumor necrosis factor-alpha promotor polymorphisms and endometriosis", J Soc Gynecol Investig, 9, pp.313~318 (2002)
- Wang L, "IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway", J Exp Med, 206, pp.1457~1464 (2009)
- Xu L, "Cutting edge : regulatory T cells induce CD4+CD25-Foxp3-T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-β", J Immunol, 178, pp.6725~6729 (2007)
- Park H, "A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17", Nat Immunol, 6, pp.1133~1141 (2005)
- Bettelli E, "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells", Nature, 441, pp.235~238 (2006)
- Mangan PR, "Transforming growth factor-beta induces development of the TH17 lineage", Nature, 441, pp.231~234 (2006)
- Rizzo R, "Impact of soluble HLA-G levels and endometrial NK cells in uterine flushing samples from primary and secondary unexplained infertile women", Int J Mol Sci, 16, pp.5510~5516 (2015)
- Chen YJ, "Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis", J Pathol, 222, pp.261~270 (2010)
