Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1999 by The Endocrine Society Role of Inflammatory Mediators in Human Endometrium during Progesterone Withdrawal

The role of progesterone (P4) in the regulation of inflammatory mediators interleukin-8 (IL-8), monocyte chemoattractant protein-1, and cyclooxygenase-2 (COX-2) and in the recruitment of leukocyte subpopulations in the endometrium has been examined, by employing a model of P4 withdrawal and maintenance in vivo. Messenger RNA and protein expression have been investigated in endometrial biopsies: 1) during the midsecretory phase (LH+8 to 10); during the maintained luteal phase (P4 administered vaginally for 4 days from LH+8) and biopsies collected 2) 24 h and 3) 48 h post withdrawal of P4; and 4) during pseudo pregnancy (lifespan of corpus luteum extended by 7 days with CG; (decidua collected from women with 5) an ectopic gestation and 6) from women undergoing first-trimester termination of pregnancy). CD56+ large granular lymphocytes remain the major leukocyte subtype, both 24 and 48 h after P4 withdrawal, and in decidua (CG supported or ectopic). Higher numbers (P < 0.05) of macrophages (CD68+) were present in endometrium 48 h post P4 withdrawal and in pseudo pregnant endometrium, compared with normal decidua. Significantly more macrophages (P < 0.01) were present in decidua from an ectopic pregnancy. A significant elevation of IL-8 (P < 0.01) and COX-2 (P < 0.05) messenger RNA was detected 48 h post P4 withdrawal. Evidence is provided for up-regulation of IL-8 and COX-2 in response to P4 withdrawal.

[1]  I. Colditz.  Effect of exogenous prostaglandin E2 and actinomycin D on plasma leakage induced by neutrophil‐activating peptide‐1/interleukin‐8 , 1990, Immunology and cell biology.

[2]  R. Lea,et al.  Macrophages and migratory cells in endometrium relevant to implantation. , 1991, Bailliere's clinical obstetrics and gynaecology.

[3]  I. Cooke,et al.  Endometrial lymphoid tissue in the timed endometrial biopsy: morphometric and immunohistochemical aspects. , 1992, American journal of obstetrics and gynecology.

[4]  L. Gardner,et al.  Evaluation of oestrogen and progesterone receptor expression in uterine mucosal lymphocytes. , 1996, Human reproduction.

[5]  A. Hartner,et al.  Differential regulation of chemokines by leukemia inhibitory factor, interleukin-6 and oncostatin M. , 1997, Kidney international.

[6]  R. Strieter,et al.  Chemokine gene expression and secretion by cytokine-activated human microvascular endothelial cells. Differential regulation of monocyte chemoattractant protein-1 and interleukin-8 in response to interferon-gamma. , 1994, The American journal of pathology.

[7]  S. Smith,et al.  Progesterone and antiprogestins, a comparison of their effect on prostaglandin production by human secretory phase endometrium and decidua. , 1987, Prostaglandins, leukotrienes, and medicine.

[8]  N. Narita,et al.  Interleukin-8 production by CD16-CD56bright natural killer cells in the human early pregnancy decidua. , 1994, Biochemical and biophysical research communications.

[9]  G. Carr,et al.  The inhibition of synthesis of a beta-chemokine, monocyte chemotactic protein-1 (MCP-1) by progesterone. , 1997, Biochemical and biophysical research communications.

[10]  S. Silverberg,et al.  Polymorphonuclear Leukocytes in the Endometrium During the Normal Menstrual Cycle , 1987, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[11]  Y. Fu,et al.  Estrogen and progesterone receptors in human decidua after RU486 treatment , 1994, Fertility and sterility.

[12]  D. Baird,et al.  Sex steroid regulation of leukocyte traffic in human decidua. , 1996, Human reproduction.

[13]  Y. W. Loke,et al.  Human implantation : cell biology and immunology , 1995 .

[14]  D. Lunny,et al.  Immunohistochemical characterization of stromal leucocytes in nonpregnant human endometrium. , 1988, American journal of reproductive immunology and microbiology : AJRIM.

[15]  J. Johnston,et al.  NAD+-dependent 15-hydroxyprostaglandin dehydrogenase activity in human endometrium. , 1980, Prostaglandins.

[16]  N. Ida,et al.  Detection of monocyte chemotactic and activating factor (MCAF) in normal blood and urine using a sensitive ELISA. , 1994, Cytokine.

[17]  D. Baird,et al.  Effect of cyclofenil on hormonal dynamics, follicular development and cervical mucus in normal and oligomenorrhoeic women. , 1992, Human reproduction.

[18]  J. Schröder,et al.  Acute inflammatory effects of a monocyte-derived neutrophil-activating peptide in rabbit skin. , 1989, Immunology.

[19]  R. Hume,et al.  The effects of mifepristone (RU486) on prostaglandin dehydrogenase in decidual and chorionic tissue in early pregnancy. , 1993, Human reproduction.

[20]  R. Kelly,et al.  Perivascular location of a chemokine interleukin-8 in human endometrium: a preliminary report. , 1994, Human reproduction.

[21]  O. Ishihara,et al.  Interleukin-1 beta-stimulated PGE2 production from early first trimester human decidual cells is inhibited by dexamethasone and progesterone. , 1995, Prostaglandins.

[22]  T. Inoue,et al.  Progesterone stimulates the induction of human endometrial CD56+ lymphocytes in an in vitro culture system. , 1996, Journal of Clinical Endocrinology and Metabolism.

[23]  J. Downie,et al.  Levels of prostaglandins in human endometrium during the normal menstrual cycle. , 1974, The Journal of physiology.

[24]  E. Leonard,et al.  Secretion by human fibroblasts of monocyte chemoattractant protein-1, the product of gene JE. , 1990, Journal of immunology.

[25]  D. Baird,et al.  Pharmacological “Rescue” of the Corpus Luteum Results in Increased Inhibin Production , 1991 .

[26]  A. Arıcı,et al.  Regulation of interleukin-8 gene expression in human endometrial cells in culture , 1993, Molecular and Cellular Endocrinology.

[27]  R. Kelly.  Pregnancy maintenance and parturition: the role of prostaglandin in manipulating the immune and inflammatory response. , 1994, Endocrine reviews.

[28]  R. Kelly,et al.  Chemokine and cyclooxygenase-2 expression in human endometrium coincides with leukocyte accumulation. , 1997, Human reproduction.

[29]  J. Kuratsu,et al.  Purification and amino acid analysis of two human glioma-derived monocyte chemoattractants , 1989, The Journal of experimental medicine.

[30]  P. Illingworth,et al.  Progesterone control of interleukin-8 production in endometrium and chorio-decidual cells underlines the role of the neutrophil in menstruation and parturition. , 1994, Human reproduction.

[31]  R. Kelly,et al.  The release of PGF2α and PGE2 from separated cells of human endometrium and decidua , 1988 .

[32]  K. Matsushima,et al.  Molecular mechanism of interleukin‐8 gene expression , 1994, Journal of leukocyte biology.

[33]  D. Baird,et al.  The effect of 17 beta-estradiol and progesterone on prostaglandin production by human endometrium maintained in organ culture. , 1980, Endocrinology.

[34]  Y. W. Loke,et al.  Immunology of human placental implantation: clinical implications of our current understanding. , 1997, Molecular medicine today.

[35]  N. Ida,et al.  A highly sensitive enzyme-linked immunosorbent assay for the measurement of interleukin-8 in biological fluids. , 1992, Journal of immunological methods.

[36]  J. Van Damme,et al.  Granulocyte chemotactic protein/interleukin-8 induces plasma leakage and neutrophil accumulation in rabbit skin. , 1989, The American journal of pathology.

[37]  Y. W. Loke,et al.  Uterine large granular lymphocytes: a possible role in embryonic implantation? , 1990, American journal of obstetrics and gynecology.

[38]  John I. Gallin,et al.  Inflammation: Basic Principles and Clinical Correlates , 1992 .

[39]  J. Warren,et al.  Expression of monocyte chemoattractant protein-1 in the corpus luteum of the rat. , 1996, Biology of reproduction.

[40]  R. Kelly,et al.  Concentrations of prostaglandins F2alpha and E2 in the endometrium throughout the human menstrual cycle, after the administration of clomiphene or an oestrogen-progestogen pill and in early pregnancy. , 1978, The Journal of endocrinology.

[41]  C. Redman,et al.  Distribution of cell adhesion molecules on CD56++, CD3-, CD16- large granular lymphocytes and endothelial cells in first-trimester human decidua. , 1993, Human reproduction.

[42]  W. Shi,et al.  Estrogen and progesterone receptors in human decidua after RU486* treatment† , 1993 .

[43]  D. Baird,et al.  Prostaglandins and menstruation. , 1996, European journal of obstetrics, gynecology, and reproductive biology.

[44]  A. Sica,et al.  Monocyte chemotactic and activating factor gene expression induced in endothelial cells by IL-1 and tumor necrosis factor. , 1990, Journal of immunology.

[45]  K. Matsushima,et al.  Suppression of interleukin 8 production by progesterone in rabbit uterine cervix. , 1994, The Biochemical journal.

[46]  J. Downie,et al.  Levels of prostaglandins in human endometrium during the normal menstrual cycle , 1974 .

[47]  E. Hausmann,et al.  Relative role of CSF‐1, MCP‐1/JE, and RANTES in macrophage recruitment during successful pregnancy , 1997, Molecular reproduction and development.

[48]  E. Appella,et al.  Human monocyte chemoattractant protein‐1 (MCP‐1) Full‐length cDNA cloning, expression in mitogen‐stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE , 1989, FEBS letters.

[49]  E. Appella,et al.  The neutrophil-activating protein (NAP-1) is also chemotactic for T lymphocytes. , 1989, Science.

[50]  Y. W. Loke,et al.  On the nature and function of human uterine granular lymphocytes. , 1991, Immunology today.

[51]  J. Damme.  Interleukin-8 and related chemotactic cytokines , 1994 .