Decreased Endometrial IL-10 Impairs Endometrial Receptivity by Downregulating HOXA10 Expression in Women with Adenomyosis

Objective The aim of this study was to investigate the potential role of IL-10 in regulating the receptivity marker HOXA10 in the endometrium of women with adenomyosis. Methods The expression levels of IL-10, HOXA-10, STAT3, and p-STAT3 in the endometrium of women with adenomyosis and controls were examined by means of western blotting and immunohistochemistry. The expression of the HOXA10 protein in Ishikawa cells treated with rIL-10 was examined by western blotting. The attachment rate of BeWo cell spheroids to Ishikawa cells treated with rIL-10 was expressed as a percentage of the total number of spheroids. Results The expression levels of HOXA10 and IL-10 in the adenomyosis group were significantly lower than those in the control group, and there was a positive correlation between HOXA10 and IL-10 protein levels in all the women examined. rIL-10 increased HOXA10 expression in a concentration- and time-dependent manner by inducing the phosphorylation of STAT3 in Ishikawa cells. Treatment with rIL-10 promoted the attachment of BeWo spheroids to Ishikawa cells, which was reversed by the inhibition of STAT3 phosphorylation. The expression of p-STAT3 in the adenomyosis group was significantly lower than that in the control group, and there was a positive correlation between IL-10 and p-STAT3 protein levels in all the women examined. Conclusions Both IL-10 and HOXA10 levels in the endometrium are significantly reduced in women with adenomyosis compared with those in control women. The phosphorylation of STAT3 has been proven to be a critical mediator between IL-10 and HOXA10, which may play critical roles in embryo implantation.

[1]  Aijun Zhang,et al.  Cytokine Profiling in the Eutopic Endometrium of Adenomyosis During the Implantation Window After Ovarian Stimulation , 2016, Reproductive Sciences.

[2]  Z. Tu,et al.  FoxM1 Directs STAT3 Expression Essential for Human Endometrial Stromal Decidualization , 2015, Scientific Reports.

[3]  P. Vercellini,et al.  Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis. , 2014, Human reproduction.

[4]  R. Behringer,et al.  STAT3 regulates uterine epithelial remodeling and epithelial-stromal crosstalk during implantation. , 2013, Molecular endocrinology.

[5]  Yue Jiang,et al.  PCAF impairs endometrial receptivity and embryo implantation by down-regulating β3-integrin expression via HOXA10 acetylation. , 2013, The Journal of clinical endocrinology and metabolism.

[6]  S. Dey,et al.  Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses. , 2013, Molecular endocrinology.

[7]  S. Kyo,et al.  Possible involvement of signal transducer and activator of transcription-3 in cell-cell interactions of peritoneal macrophages and endometrial stromal cells in human endometriosis. , 2013, Fertility and sterility.

[8]  L. Liao,et al.  Nuclear receptor coactivator-6 attenuates uterine estrogen sensitivity to permit embryo implantation. , 2012, Developmental cell.

[9]  Giuseppe Benagiano,et al.  The pathophysiology of uterine adenomyosis: an update. , 2012, Fertility and sterility.

[10]  T. Singer,et al.  The effects of interleukin-6 signal blockade on fertility, embryo-fetal development, and immunization in vivo. , 2012, Birth defects research. Part B, Developmental and reproductive toxicology.

[11]  Yuquan Wei,et al.  Proteomics Identification of Annexin A2 as a Key Mediator in the Metastasis and Proangiogenesis of Endometrial Cells in Human Adenomyosis* , 2012, Molecular & Cellular Proteomics.

[12]  G. Benagiano,et al.  Infertility and Adenomyosis , 2011, Obstetrics and gynecology international.

[13]  E. Asselin,et al.  Bridging endometrial receptivity and implantation: network of hormones, cytokines, and growth factors. , 2011, The Journal of endocrinology.

[14]  L. Salamonsen,et al.  Human chorionic gonadotrophin regulates FGF2 and other cytokines produced by human endometrial epithelial cells, providing a mechanism for enhancing endometrial receptivity. , 2011, Human reproduction.

[15]  H. Taylor,et al.  HOXA10 expression is decreased in endometrium of women with adenomyosis. , 2010, Fertility and sterility.

[16]  Yingfang Zhou,et al.  Leukemia inhibitory factor is dysregulated in the endometrium and uterine flushing fluid of patients with adenomyosis during implantation window. , 2010, Fertility and sterility.

[17]  Zhongli Yang,et al.  Expression of interleukin-10 in patients with adenomyosis. , 2009, Fertility and sterility.

[18]  J. O’Shea,et al.  Cytokine signaling modules in inflammatory responses. , 2008, Immunity.

[19]  T. Strowitzki,et al.  The human endometrium as a fertility-determining factor. , 2006, Human reproduction update.

[20]  J. Styles,et al.  Neonatal tamoxifen treatment of mice leads to adenomyosis but not uterine cancer. , 2005, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[21]  H. Taylor,et al.  The Role of HOX Genes in Human Implantation , 2004, Annals of the New York Academy of Sciences.

[22]  Toshinobu Tanaka,et al.  Stromal vascularization in the endometrium during adenomyosis , 2003, Microscopy research and technique.

[23]  H. Kliman,et al.  Maternal Hoxa10 is required for pinopod formation in the development of mouse uterine receptivity to embryo implantation , 2001, Developmental dynamics : an official publication of the American Association of Anatomists.

[24]  H. Hohn,et al.  Adhesion of trophoblast to uterine epithelium as related to the state of trophoblast differentiation: In vitro studies using cell lines , 2000, Molecular reproduction and development.

[25]  L. Robb,et al.  Expression of interleukin-11 during the human menstrual cycle: coincidence with stromal cell decidualization and relationship to leukaemia inhibitory factor and prolactin. , 2000, Molecular human reproduction.

[26]  P. Igarashi,et al.  In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing mullerian system , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  J. Hatazawa,et al.  Immunohistochemical assessment of superoxide dismutase expression in the endometrium in endometriosis and adenomyosis. , 1999, Fertility and sterility.

[28]  V. Guiard,et al.  © 1999 The Japanese Society for Immunology IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes , 2022 .

[29]  H. Taylor,et al.  HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium. , 1998, The Journal of clinical investigation.

[30]  C. Begley,et al.  Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation , 1998, Nature Medicine.

[31]  H. Taylor,et al.  A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. , 1997, Biology of reproduction.

[32]  R. Maas,et al.  Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. , 1996, Development.

[33]  R. Maas,et al.  Sexually dimorphic sterility phenotypes in HoxalO-deficient mice , 1995, Nature.

[34]  Colin Stewart,et al.  The Role of Leukemia Inhibitory Factor (LIF) and Other Cytokines in Regulating Implantation in Mammals , 1994, Annals of the New York Academy of Sciences.

[35]  T. Mosmann,et al.  Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones , 1989, The Journal of experimental medicine.

[36]  P. Collinet,et al.  An update on adenomyosis. , 2013, Diagnostic and interventional imaging.

[37]  L. Salamonsen,et al.  Local regulation of implantation at the human fetal-maternal interface. , 2010, The International journal of developmental biology.

[38]  H. Taylor,et al.  HOXA10, Pbx2, and Meis1 protein expression in the human endometrium: formation of multimeric complexes on HOXA10 target genes. , 2005, The Journal of clinical endocrinology and metabolism.

[39]  I. Cooke,et al.  The role of T-helper cytokines in human reproduction. , 2000, Fertility and sterility.