Downregulation of cilia-localized Il-6R alpha by 17beta-estradiol in mouse and human fallopian tubes.

The action of interleukin-6 (IL-6) impacts female reproduction. Although IL-6 was recently shown to inhibit cilia activity in human fallopian tubes in vitro, the molecular mechanisms underlying IL-6 signaling to tubal function remain elusive. Here, we investigate the cellular localization, regulation, and possible function of two IL-6 receptors (IL-6R alpha and gp130) in mouse and human fallopian tubes in vivo. We show that IL-6R alpha is restricted to the cilia of epithelial cells in both mouse and human fallopian tubes. Exogenous 17beta-estradiol (E(2)), but not progesterone (P(4)), causes a time-dependent decrease in IL-6R alpha expression, which is blocked by the estrogen receptor (ER) antagonist ICI-182,780. Exposure of different ER-selective agonists propyl-(1H)-pyrazole-1,3,5-triyl-trisphenol or 2,3-bis-(4-hydroxyphenyl)-propionitrile demonstrated an ER subtype-specific regulation of IL-6R alpha in mouse fallopian tubes. In contrast to IL-6R alpha, gp130 was detected in tubal epithelial cells in mice but not in humans. In humans, gp130 was found in the muscle cells and was decreased in the periovulatory and luteal phases during the reproductive cycles, indicating a species-specific expression and regulation of gp130 in the fallopian tube. Expression of tubal IL-6R alpha and gp130 in IL-6 knockout mice was found to be normal; however, E(2) treatment increased IL-6R alpha, but not gp130, in IL-6 knockout mice when compared with wild-type mice. Furthermore, expression levels of IL-6R alpha, but not gp130, decreased in parallel with estrogenic accelerated oocyte-cumulus complex (OCC) transport in mouse fallopian tubes. Our findings open the possibility that cilia-specific IL-6R alpha may play a role in the regulation of OCC transport and suggest an estrogen-regulatory pathway of IL-6R alpha in the fallopian tube.

[1]  B. Weijdegård,et al.  Clomiphene Citrate Causes Aberrant Tubal Apoptosis and Estrogen Receptor Activation in Rat Fallopian Tube: Implications for Tubal Ectopic Pregnancy1 , 2009, Biology of reproduction.

[2]  C. Ling,et al.  Differences in Prolactin Receptor (PRLR) in Mouse and Human Fallopian Tubes: Evidence for Multiple Regulatory Mechanisms Controlling PRLR Isoform Expression in Mice1 , 2008, Biology of reproduction.

[3]  R. A. Lyons,et al.  The effect of interleukin-6 on ciliary beat frequency in the human fallopian tube. , 2008, Fertility and sterility.

[4]  R. Tribe,et al.  Cytokine Networks and the Regulation of Uterine Function in Pregnancy and Parturition , 2008, Journal of neuroendocrinology.

[5]  W. Bremner,et al.  Advances in male contraception. , 2008, Endocrine reviews.

[6]  H. Croxatto,et al.  Catechol-O-Methyltransferase and Methoxyestradiols Participate in the Intraoviductal Nongenomic Pathway Through Which Estradiol Accelerates Egg Transport in Cycling Rats1 , 2007, Biology of reproduction.

[7]  G. Chaouat,et al.  Cytokines: Important for implantation? , 2007, Journal of Assisted Reproduction and Genetics.

[8]  N. Andersson,et al.  Dynamic regulation of estrogen receptor-alpha isoform expression in the mouse fallopian tube: mechanistic insight into estrogen-dependent production and secretion of insulin-like growth factors. , 2007, American journal of physiology. Endocrinology and metabolism.

[9]  H. Omran,et al.  When cilia go bad: cilia defects and ciliopathies , 2007, Nature Reviews Molecular Cell Biology.

[10]  N. Sumar,et al.  Cytokine profiles in serum and peritoneal fluid from infertile women with and without endometriosis , 2007, The journal of obstetrics and gynaecology research.

[11]  R. Straub,et al.  The complex role of estrogens in inflammation. , 2007, Endocrine reviews.

[12]  Changlian Zhu,et al.  Ciliated epithelial-specific and regional-specific expression and regulation of the estrogen receptor-beta2 in the fallopian tubes of immature rats: a possible mechanism for estrogen-mediated transport process in vivo. , 2007, American journal of physiology. Endocrinology and metabolism.

[13]  A. Romano,et al.  Estrogen and the endometrium: lessons learned from gene expression profiling in rodents and human. , 2007, Human reproduction update.

[14]  A. Stavreus-Evers,et al.  Leukaemia inhibitory factor receptor and gp130 in the human Fallopian tube and endometrium before and after mifepristone treatment and in the human preimplantation embryo. , 2007, Molecular human reproduction.

[15]  Tomomi Sato,et al.  Gene Expression Change in the Müllerian Duct of the Mouse Fetus Exposed to Diethylstilbestrol In Utero , 2007, Experimental biology and medicine.

[16]  Fu-Ping Zhang,et al.  Estrogen-induced upregulation of AR expression and enhancement of AR nuclear translocation in mouse fallopian tubes in vivo. , 2007, American journal of physiology. Endocrinology and metabolism.

[17]  K. Korach,et al.  Potential Biological Functions Emerging from the Different Estrogen Receptors , 2006, Annals of the New York Academy of Sciences.

[18]  T. Kishimoto,et al.  Interleukin-6 : discovery of a pleiotropic cytokine , 2022 .

[19]  Changlian Zhu,et al.  Nuclear progesterone receptor A and B isoforms in mouse fallopian tube and uterus: implications for expression, regulation, and cellular function. , 2006, American journal of physiology. Endocrinology and metabolism.

[20]  R. A. Lyons,et al.  The reproductive significance of human Fallopian tube cilia. , 2006, Human reproduction update.

[21]  J. Scheller,et al.  Interleukin-6 and its receptor: from bench to bedside , 2006, Medical Microbiology and Immunology.

[22]  M. Asashima,et al.  Ciliated Cells Differentiated from Mouse Embryonic Stem Cells , 2006, Stem cells.

[23]  S. Nielsen,et al.  Distribution of sodium transporters and aquaporin‐1 in the human choroid plexus , 2006, American journal of physiology. Cell physiology.

[24]  C. White,et al.  Cytokines, chemokines and growth factors in endometrium related to implantation. , 2005, Human reproduction update.

[25]  T. Schaefer,et al.  Secretion of cytokines and chemokines by polarized human epithelial cells from the female reproductive tract. , 2005, Human reproduction.

[26]  K. Korach,et al.  Lessons in estrogen biology from knockout and transgenic animals. , 2005, Annual review of physiology.

[27]  K. Korach,et al.  Estrogen Receptors: Structure, Mechanisms and Function , 2002, Reviews in Endocrine and Metabolic Disorders.

[28]  A. Zenclussen,et al.  Murine abortion is associated with enhanced interleukin-6 levels at the feto-maternal interface. , 2003, Cytokine.

[29]  E. Darai,et al.  Serum concentrations of interleukin-2R (IL-2R), IL-6, IL-8, and tumor necrosis factor alpha in patients with ectopic pregnancy. , 2003, Fertility and Sterility.

[30]  H. Billig,et al.  Expression of Progesterone Receptor (PR) A and B Isoforms in Mouse Granulosa Cells: Stage-Dependent PR-Mediated Regulation of Apoptosis and Cell Proliferation1 , 2003, Biology of reproduction.

[31]  Miguel Rios,et al.  Expression of Proinflammatory Cytokines and Receptors by Human Fallopian Tubes in Organ Culture following Challenge with Neisseria gonorrhoeae , 2003, Infection and Immunity.

[32]  U. Lerner,et al.  IL-6, Leukemia Inhibitory Factor, and Oncostatin M Stimulate Bone Resorption and Regulate the Expression of Receptor Activator of NF-κB Ligand, Osteoprotegerin, and Receptor Activator of NF-κB in Mouse Calvariae1 , 2002, The Journal of Immunology.

[33]  J. Pfeilschifter,et al.  Changes in proinflammatory cytokine activity after menopause. , 2002, Endocrine reviews.

[34]  H. Croxatto,et al.  Physiology of gamete and embryo transport through the fallopian tube. , 2002, Reproductive biomedicine online.

[35]  B. Katzenellenbogen,et al.  Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. , 2001, Journal of medicinal chemistry.

[36]  A. Zenclussen,et al.  During Pregnancy, in the Context of a Th2‐Type Cytokine Profile, Serum IL‐6 Levels Might Condition the Quality of the Synthesized Antibodies , 2001, American journal of reproductive immunology.

[37]  H. Leese,et al.  Formation of Fallopian tubal fluid: role of a neglected epithelium. , 2001, Reproduction.

[38]  B. Katzenellenbogen,et al.  Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. , 2000, Journal of medicinal chemistry.

[39]  B. O’Malley,et al.  Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[40]  G. Gibori,et al.  The Expression of Interleukin-6 (IL-6), IL-6 Receptor, and gp130-Kilodalton Glycoprotein in the Rat Decidua and a Decidual Cell Line: Regulation by 17β-Estradiol and Prolactin1. , 1999, Endocrinology.

[41]  S. C. Lin,et al.  Regulation of the gp80 and gp130 subunits of the IL-6 receptor by sex steroids in the murine bone marrow. , 1997, The Journal of clinical investigation.

[42]  A. Ray,et al.  Repression of interleukin‐6 gene expression by 17β‐estradiol: , 1997 .

[43]  L. D. Ward,et al.  Interleukin‐6: Structure‐function relationships , 1997, Protein science : a publication of the Protein Society.

[44]  N. Terakawa,et al.  Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis. , 1997, American journal of obstetrics and gynecology.

[45]  K. Grandien,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors � and � , 2022 .

[46]  J. Lippes,et al.  Cytokines of the Human Reproductive Tract , 1996, American journal of reproductive immunology.

[47]  H. Abe.  The mammalian oviductal epithelium: regional variations in cytological and functional aspects of the oviductal secretory cells. , 1996, Histology and histopathology.

[48]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[49]  B Stein,et al.  Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta , 1995, Molecular and cellular biology.

[50]  D. Émilie,et al.  Interleukin-6 biosynthesis in human preovulatory follicles: some of its potential roles at ovulation. , 1994, The Journal of clinical endocrinology and metabolism.

[51]  R. Zinkernagel,et al.  Impaired immune and acute-phase responses in interleukin-6-deficient mice , 1994, Nature.

[52]  T. Hirano,et al.  Molecular cloning and expression of an IL-6 signal transducer, gp130 , 1990, Cell.

[53]  S. Halbert,et al.  Ovum transport in the rat oviductal ampulla in the absence of muscle contractility. , 1989, Biology of reproduction.

[54]  R. Norman,et al.  Impaired corpus luteum function in ectopic pregnancy cannot be explained by altered human chorionic gonadotropin. , 1988, The Journal of clinical endocrinology and metabolism.

[55]  R. Romero,et al.  Progesterone, estradiol, and alpha-human chorionic gonadotropin secretion in patients with ectopic pregnancy. , 1986, The Journal of clinical endocrinology and metabolism.

[56]  P. Chambon,et al.  Cloning of the human oestrogen receptor cDNA. , 1986, Journal of steroid biochemistry.

[57]  R. Jansen.  Endocrine response in the fallopian tube. , 1984, Endocrine reviews.

[58]  H. Croxatto,et al.  Ovum transport and fertility following postovulatory treatment with estradiol in rats. , 1979, Biology of reproduction.

[59]  Blandau Rj.  Comparative aspects of tubal anatomy and physiology as they relate to reconstructive procedures. , 1978 .

[60]  R. Blandau,et al.  Egg transport in the rabbit oviduct: the roles of cilia and muscle. , 1976, Science.