title: IL-33 enhances proliferation and invasiveness of decidual stromal cells by up-regulation of CCL2/CCR2 via NF-κB and ERK1/2 signaling.
abstract: Interleukin (IL)-33, a newly described member of the IL-1 family, has been reported to facilitate primary tumor progression and metastatic dissemination. However, its biological function on decidual stromal cells (DSCs) remains unclear. In this study, we tested the hypothesis whether IL-33 promotes proliferation and invasion of DSCs, and the possible mechanism. IL-33 and its orphan receptor ST2 was found to be co-expressed by DSCs in human first-trimester pregnancy. Addition of IL-33, enhanced the proliferation and invasion of DSCs in a dosage-dependent manner, concomitantly with increasing expression of proliferation relative gene (PCNA, survivin) and invasion relative gene (titin, MMP2). Blocking IL-33/ST2 signaling by soluble sST2 apparently abolished the stimulatory effect on the proliferation, invasiveness and related gene expression in DSCs. We also demonstrated that chemokines CCL2/CCR2 was significantly increased with IL-33 administration. Moreover, inhibition of CCL2/CCR2 activation using CCL2 neutralizing antibody or CCR2 blocker prevented IL-33-stimulated proliferation and invasiveness capacity of DSCs. Increasing phosphorylation of nuclear factor NF-κB p65 and extracellular signal-regulated kinases ERK1/2 after treatment with IL-33 was confirmed by western blotting. And the IL-33-induced CCL2/CCR2 expression was abrogated by treatment with the NF-κB inhibitor BAY 11-7082 or ERK1/2 inhibitor U0126. Finally, we showed that decreased IL-33/ST2 expression was observed in DSCs from spontaneous abortion compared with normal pregnancy at both gene and protein levels. This study provides evidence for the molecular mechanism of IL-33 in promoting proliferation and invasiveness of DSCs by up-regulation of CCL2/CCR2 via NF-κB and ERK1/2 signal pathways and thus contributes insight to the potential of IL-33 involved in successful pregnancy via inducing DSCs mitosis and invasion.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Hu
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Jin
authors.forename: Da-Jin
authors.initials: DJ
authors.lastname: Li
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Zhu
mesh_terms: D000328:Adult; D000906:Antibodies / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D061251:Primary Cell Culture; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D000077022:Survivin
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000906:Antibodies; C107489:BIRC5 protein, human; D002070:Butadienes; C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; C506536:IL33 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000067596:Interleukin-33; D007378:Interleukins; D016328:NF-kappa B; D009570:Nitriles; D018809:Proliferating Cell Nuclear Antigen; D054390:Receptors, CCR2; D013450:Sulfones; D000077022:Survivin; C113580:U 0126; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: CCL2; IL-33; decidual stromal cells; invasion; proliferation