IL-23 Inhibits Trophoblast Proliferation, Migration, and EMT via Activating p38 MAPK Signaling Pathway to Promote Recurrent Spontaneous Abortion
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As a vital problem in reproductive health, recurrent spontaneous abortion (RSA) affects about 1% of women. We performed this study with an aim to explore the molecular mechanism of interleukin-23 (IL-23) and find optimal or effective methods to improve RSA. First, ELISA was applied to evaluate the expressions of IL-23 and its receptor in HTR-8/SVneo cells after IL-23 treatment. CCK-8, TUNEL, wound healing and transwell assays were employed to assess the proliferation, apoptosis, migration and invasion of HTR-8/SVneo cells, respectively. Additionally, the expressions of apoptosis-, migration-, epithelial-mesenchymal transition- (EMT-) and p38 MAPK signaling pathway-related proteins were measured by western blotting. To further investigate the relationship between IL-23 and p38 MAPK signaling pathway, HTR-8/SVneo cells were treated for 1 h with p38 MAPK inhibitor SB239063, followed by a series of cellular experiments on proliferation, apoptosis, migration and invasion, as aforementioned. The results showed that IL-23 and its receptors were greatly elevated in IL-23-treated HTR-8/SVneo cells. Additionally, IL-23 demonstrated suppressive effects on the proliferation, apoptosis, migration, invasion and EMT of IL-23-treated HTR-8/SVneo cells. More importantly, the molecular mechanism of IL-23 was revealed in this study; that is to say, IL-23 inhibited the proliferation, apoptosis, migration, invasion and EMT of IL-23-treated HTR-8/SVneo cells via activating p38 MAPK signaling pathway. In conclusion, IL-23 inhibits trophoblast proliferation, migration, and EMT via activating p38 MAPK signaling pathway, suggesting that IL-23 might be a novel target for the improvement of RSA.
Abstract
As a vital problem in reproductive health, recurrent spontaneous abortion (RSA) affects about 1% of women. We performed this study with an aim to explore the molecular mechanism of interleukin-23 (IL-23) and find optimal or effective methods to improve RSA. First, ELISA was applied to evaluate the expressions of IL-23 and its receptor in HTR-8/SVneo cells after IL-23 treatment. CCK-8, TUNEL, wound healing and transwell assays were employed to assess the proliferation, apoptosis, migration and invasion of HTR-8/SVneo cells, respectively. Additionally, the expressions of apoptosis-, migration-, epithelial-mesenchymal transition- (EMT-) and p38 MAPK signaling pathway-related proteins were measured by western blotting. To further investigate the relationship between IL-23 and p38 MAPK signaling pathway, HTR-8/SVneo cells were treated for 1 h with p38 MAPK inhibitor SB239063, followed by a series of cellular experiments on proliferation, apoptosis, migration and invasion, as aforementioned. The results showed that IL-23 and its receptors were greatly elevated in IL-23-treated HTR-8/SVneo cells. Additionally, IL-23 demonstrated suppressive effects on the proliferation, apoptosis, migration, invasion and EMT of IL-23-treated HTR-8/SVneo cells. More importantly, the molecular mechanism of IL-23 was revealed in this study; that is to say, IL-23 inhibited the proliferation, apoptosis, migration, invasion and EMT of IL-23-treated HTR-8/SVneo cells via activating p38 MAPK signaling pathway. In conclusion, IL-23 inhibits trophoblast proliferation, migration, and EMT via activating p38 MAPK signaling pathway, suggesting that IL-23 might be a novel target for the improvement of RSA.
참고문헌 (39)
- RPL EGGo, "ESHRE guideline: recurrent pregnancy loss", Human Reproduction Open, 2018(2) (2018), Oxford University Press (OUP)[DOI]
- de Moreuil C, "Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage", Br. J. Clin. Pharmacol, 86, pp.39~49 (2020)
- Larsen EC, "New insights into mechanisms behind miscarriage", BMC Med, 11, pp.154~ (2013)
- Grande M, "The effect of maternal age on chromosomal anomaly rate and spectrum in recurrent miscarriage", Hum. Reprod, 27, pp.3109~3117 (2012)
- Garrido-Gimenez C, "Recurrent miscarriage : causes, evaluation and management", Postgrad. Med. J, 91, pp.151~162 (2015)
- Oppmann B, "Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12", Immunity, 13, pp.715~725 (2000)
- Becker C, "Constitutive p40 promoter activation and IL-23production in the terminal ileum mediated by dendritic cells", J. Clin. Invest, 112, pp.693~706 (2003)
- Tonel G, "Cutting edge : A critical functional role for IL-23 in psoriasis", J. Immunol, 185, pp.5688~5691 (2010)
- Teng MW, "IL-12 and IL-23 cytokines : from discovery to targeted therapies for immune-mediated inflammatory diseases", Nat. Med, 21, pp.719~729 (2015)
- Tang C, "Interleukin-23 : as a drug target for autoimmune inflammatory diseases", Immunology, 135, pp.112~124 (2012)
- Li N, "Women with recurrent spontaneous abortion have decreased 25(OH)vitamin D and VDR at the fetal-maternal interface", Braz. J. Med. Biol. Res, 50, pp.e6527~ (2017)
- Eaton LH, "Interleukin-17 and interleukin-23 regulate Langerhans cell migration", Br. J. Dermatol, 175, pp.622~624 (2016)
- Coulthard LR, "p38(MAPK) : stress responses from molecular mechanisms to therapeutics", Trends Mol. Med, 15, pp.369~379 (2009)
- Arthur JS, "Mitogen-activated protein kinases in innate immunity", Nat. Rev. Immunol, 13, pp.679~692 (2013)
- Yong HY, "The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer", Expert Opin. Investig. Drugs, 18, pp.1893~1905 (2009)
- Ono K, "The p38 signal transduction pathway : activation and function", Cell. Signal, 12, pp.1~13 (2000)
- Yu L, "TGF-beta receptor-activated p38 MAP kinase mediates smad-independent TGF-β responses", EMBO J, 21, pp.3749~3759 (2002)
- Seshadri S, "Bacillus anthracis lethal toxin negatively modulates ILC3 function through perturbation of IL-23-mediated MAPK signaling", PLoS Pathog, 13, pp.e1006690~ (2017)
- Gao P, "G-CSF : A vehicle for communication between trophoblasts and macrophages which may cause problems in recurrent spontaneous abortion", Placenta, 121, pp.164~172 (2022)
- Wu L, "CRY2 suppresses trophoblast migration and invasion in recurrent spontaneous abortion", J. Biochem, 167, pp.79~87 (2020)
- Lamptey J, "Downregulation of fascin in the first trimester placental villi is associated with early recurrent miscarriage", Exp. Cell Res, 403, pp.112597~ (2021)
- Gu Y, "Anti-atherosclerotic effect of afrocyclamin A against vascular smooth muscle cells is mediated via p38 MAPK signaling pathway", Cell J, 23, pp.191~198 (2021)
- Guenther S, "Decidual macrophages are significantly increased in spontaneous miscarriages and over-express FasL : a potential role for macrophages in trophoblast apoptosis", Int. J. Mol. Sci, 13, pp.9069~9080 (2012)
- Red-Horse K, "Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface", J. Clin. Invest, 114, pp.744~754 (2004)
- Li M, "Long non-coding RNA IGF2-AS promotes trophoblast cell proliferation, migration, and invasion by regulating miR-520g", N-cadherin axis, 2021, pp.47, 3047~3059
- Bulmer JN, "Immune cells in the placental bed", Int. J. Dev. Biol, 54, pp.281~294 (2010)
- Zong S, "Dysregulated expression of IDO may cause unexplained recurrent spontaneous abortion through suppression of trophoblast cell proliferation and migration", Sci. Rep, 6, pp.19916~ (2016)
- Huang W, "Effects of cyclosporine A on proliferation, invasion and migration of HTR-8", SVneo human extravillous trophoblasts, 2020, pp.533, 645~650
- Li Z, "Effect of STOX1 on recurrent spontaneous abortion by regulating trophoblast cell proliferation and migration via the PI3K", AKT signaling pathway, 2018, pp.120, 8291~8299
- Li S, "BMAL1 facilitates trophoblast migration and invasion via SP1-DNMT1", DAB2IP pathway in recurrent spontaneous abortion, 2017, pp.8, 89451~89464
- Liang H, "MSX2 Induces trophoblast invasion in human placenta", PLoS One, 11, pp.e0153656~ (2016)
- Kalluri R, "The basics of epithelial-mesenchymal transition", J. Clin. Invest, 119, pp.1420~1428 (2009)
- Heerboth S, "EMT and tumor metastasis", Clin. Transl. Med, 4, pp.6~ (2015)
- Lamouille S, "Molecular mechanisms of epithelial-mesenchymal transition", Nat. Rev. Mol. Cell Biol, 15, pp.178~196 (2014)
- Zhang S, "CXCL5 Downregulation in villous tissue is correlated with recurrent spontaneous abortion", Front. Immunol, 12, pp.717483~ (2021)
- Kim MS, "p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells", Cancer Res, 63, pp.5454~5461 (2003)
- Wang Z, "NOD1 and NOD2 control the invasiveness of trophoblast cells via the MAPK", p38 signaling pathway in human first-trimester pregnancy, 2015, pp.36, 652~660
- Hui Zhao, "LncRNA LINC01088 inhibits the function of trophoblast cells, activates the MAPK-signaling pathway and associates with recurrent pregnancy loss", Molecular Human Reproduction, 27(8) (2021), Oxford University Press (OUP)[DOI]
- Underwood DC, "SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence", J. Pharmacol. Exp. Ther, 293, pp.281~288 (2000)