Interleukin-1 receptor antagonist blocks interleukin-1– induced expression of cyclooxygenase-2 in endometrium


      Objective: Our purpose was to test the hypothesis that the interleukin-1 receptor antagonist can inhibit interleukin-1–induced prostaglandin production and de novo expression of the inducible cyclooxygenase-2 isoform in a human endometrial epithelial cell line. Study design: A continuous line of human endometrial epithelial cells was established from a hysterectomy specimen from a nonmalignant uterus. Cells were maintained as a monolayer culture in medium 199 supplemented with 10% fetal bovine serum and 50 μg/ml gentamicin. Cultures were treated with cytokines (interleukin-1α or interleukin-1β, interleukin-1 receptor antagonist, or tumor necrosis factor-α), and media were collected for analysis of prostaglandin E2 and prostaglandin F) by radioimmunoassay, whereas cells were harvested for ribonucleic acid and protein extractions and subsequent Northern blot or Western blot analyses, respectively. Results: When endometrial cells were incubated with interleukin-1α or interleukin-1β, each cytokine was shown to stimulate the production of prostaglandin E2 and prostaglandin F in a time- and dose-dependent fashion, with interleukin-1α being far more potent than interleukin-1β. Interleukin-1 receptor antagonist inhibited interleukin-1α– and interleukin-1β–induced prostaglandin formation, with 50% inhibitory concentration values of 30 ng/ml for prostaglandin E2 and 90 ng/ml for prostaglandin F. When Northern blots of interleukin-1α–treated cells were probed with a complementary deoxyribonucleic acid fragment specific for either cyclooxygenase-1 or cyclooxygenase-2, rapid de novo induction of cyclooxygenase-2 messenger ribonucleic acid was observed; however, cyclooxygenase-1 expression was constant regardless of interleukin-1α concentration or incubation time. Coincubation of cells with interleukin-1α (10 ng/ml) and cycloheximide caused superinduction of cyclooxygenase-2 messenger ribonucleic acid but had no effect on the expression of cyclooxygenase-1 messenger ribonucleic acid. Actinomycin D completely abolished interleukin-1α–induced cyclooxygenase-2 messenger ribonucleic acid expression, suggesting that the cytokine caused transcriptional activation of the cyclooxygenase-2 gene. Experiments were conducted to examine whether interleukin-1 receptor antagonist could suppress interleukin-1–induced cyclooxygenase-2 expression. Cells were preincubated for 30 minutes with interleukin-1 receptor antagonist and then challenged with interleukin-1α. Northern and Western analyses revealed that interleukin-1 receptor antagonist blocked interleukin-1α–induced expression of cyclooxygenase-2 messenger ribonucleic acid transcripts and the subsequent appearance of cyclooxygenase-2 protein. Interleukin-1 receptor antagonist had no effect on the constitutive expression of cyclooxygenase-1 messenger ribonucleic acid and protein. Interleukin-1 receptor antagonist failed to alter prostaglandin E2 formation in response to tumor necrosis factor-α, indicating that the antagonist is specific for interleukin-1 family cytokines. Finally, interleukin-1 receptor antagonist acted as a partial agonist in some experiments in that relatively high concentrations (>100 ng/ml) caused a modest increase in prostaglandin E2 and F production. CONCLUSIONS: These data indicate that interleukin-1 receptor antagonist is a potent inhibitor of interleukin-1-induced arachidonic acid metabolism and could possibly serve as an endogenous or exogenous modulator of interleukin-1 action in the endometrial epithelium.


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        • Fay TN
        • Grudzinskas JG
        Human endometrial peptides: a review of their potential role in implantation and placentation.
        Hum Reprod. 1991; 6: 1311-1326
        • Smith SK
        Growth factors in the human endometrium.
        Hum Reprod Update. 1994; 9: 936-946
        • Smith SK
        • Kelly RW
        The release of PGF and PGF2 from separated cells of human endometrium and decidua.
        Prostaglandins Leukotrienes Essent Fatty Acids. 1988; 33: 91-96
        • Schatz F
        • Markiewicz L
        • Gurpide E
        Hormonal effects of PGF output by cultures of epithelial and stromal cells in human endometrium.
        J Steroid Biochem. 1986; 24: 297-301
        • Cameron IT
        Prostaglandins and menstruation.
        in: Prostaglandins and the uterus. Springer-Verlag, London1992: 17-32
        • Lumsden MA
        Prostaglandins in dysmenorrhoea and endometriosis.
        in: Prostaglandins and the uterus. Springer-Verlag, London1992: 45-66
        • Gupta A
        • Huet YM
        • Dey SK
        Evidence for prostaglandins and leukotrienes as mediators of phase I of estrogen action in implantation in the mouse.
        Endocrinology. 1989; 124: 546-548
        • Frank GR
        • Brar AK
        • Cedars MI
        • Handwerger S
        Prostaglandin E2 enhances human endometrial stromal cell differentiation.
        Endocrinology. 1994; 134: 258-263
        • Simon C
        • Piquette GN
        • Frances A
        • Polan ML
        Localization of interleukin-1 type I receptor and interleukin-1β in human endometrium throughout the menstrual cycle.
        J Clin Endocrinol Metab. 1993; 77: 549-555
        • Tabibzadeh S
        • Kaffka KL
        • Satyaswaroop PG
        • Kilian PL
        Interleukin-1 (IL-1) regulation of human endometrial function: presence of IL-1 receptor correlates with IL-1-stimulated prostaglandin E2 production.
        J Clin Endocrinol Metab. 1990; 70: 1000-1006
        • Kennard EA
        • Zimmerman PD
        • Friedman CI
        • Kniss DA
        Interleukin-1β induces cyclooxygenase-2 in cultured human decidual cells.
        Am J Reprod Immunol. 1995; 34: 65-71
        • Simon C
        • Frances A
        • Piquette GN
        • Danasouri IE
        • Zurawski G
        • Dang W
        • et al.
        Embryonic implantation in mice is blocked by interleukin-1 receptor antagonist.
        Endocrinology. 1994; 134: 521-528
        • Arend WP
        Interleukin 1 receptor antagonist: a new member of the interleukin 1 family.
        J Clin Invest. 1991; 88: 1445-1451
        • Albert TJ
        • Su H-C
        • Zimmerman PD
        • Iams JD
        • Kniss DA
        Interleukin-1β regulates the inducible cyclooxygenase in amnion-derived WISH cells.
        Prostaglandins. 1994; 48: 401-416
        • Daly DC
        • Maslar IA
        • Riddick DH
        Prolactin production during in vitro decidualization of proliferative endometrium.
        Am J Obstet Gynecol. 1983; 145: 672-678
        • Ryan IP
        • Schroick ED
        • Taylor RN
        Isolation, characterization, and comparison of human endometrial and endometriosis cells in vitro.
        J Clin Endocrinol Metab. 1994; 78: 642-649
        • DeWitt DL
        Prostaglandin endoperoxide synthase: regulation of enzyme expression.
        Biochim Biophys Acta. 1991; 1083: 121-134
        • Wilborn J
        • Crofford LJ
        • Burdick MD
        • Kunkel SL
        • Strieter RM
        • Peters-Golden M
        Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2.
        J Clin Invest. 1995; 95: 1861-1868
        • Gershenwald JE
        • Fong Y
        • Fahey III, TJ
        • Calvano SE
        • Chizzonite R
        • Kilian PL
        • et al.
        Interleukin 1 receptor blockade attenuates the host inflammatory response.
        Proc Natl Acad Sci U S A. 1990; 87: 4966-4970
        • Wakabayashi G
        • Gelfand JA
        • Burke JF
        • Thompson RC
        • Dinarello CA
        A specific receptor antagonist for interleukin 1 prevents Escherichia coli–induced shock in rabbits.
        FASEB J. 1991; 5: 338-343
        • Vogels MTE
        • Mensink EJBM
        • Ye K
        • Boerman OC
        • Verschueren CMM
        • Dinarello CA
        • et al.
        Differential gene expression of IL-1 receptor antagonist, IL-1, and TNF receptors and IL-1 and TNF synthesis may explain IL-1-induced resistance to infection.
        J Immunol. 1994; 153: 5772-5780
        • Romero R
        • Tartakovsky B
        The natural interleukin-1 receptor antagonist prevents interleukin-1-induced preterm delivery in mice.
        Am J Obstet Gynecol. 1992; 167: 1041-1045
        • Romero R
        • Sepulveda W
        • Mazor M
        • Brandt F
        • Cotton DB
        • Dinarello CA
        • et al.
        The natural interleukin-1 receptor antagonist in term and preterm parturition.
        Am J Obstet Gynecol. 1992; 167: 863-872
        • Fidel Jr, PL
        • Romero R
        • Ramirez M
        • Cutright J
        • Edwin SS
        • LaMarchie S
        • et al.
        Interleukin-1 receptor antagonist (IL-ra) production by human amnion, chorion, and decidua.
        Am J Reprod Immunol. 1994; 32: 1-7
        • Dudley DJ
        • Chen C-L
        • Branch DW
        • Hammond E
        • Mitchell MD
        A murine model of preterm labor: inflammatory mediators regulate the production of prostaglandin E2 and interleukin-6 by murine decidua.
        Biol Reprod. 1993; 48: 33-39
        • Silver RM
        • Edwin SS
        • Trautman MS
        • Simmons DL
        • Branch DW
        • Dudley DJ
        • et al.
        Bacterial lipopolysaccharide-mediated fetal death: production of a newly recognized form of inducible cyclooxygenase (COX-2) in murine decidua in response to lipopolysaccharide.
        J Clin Invest. 1995; 95: 725-731
        • Swaisgood CM
        • Zu H-X
        • Perkins DJ
        • Wu S
        • Garver CL
        • Zimmerman PD
        • et al.
        Coordinate expression of inducible nitric oxide synthase and cyclooxygenase-2 genes in uterine tissues of endotoxin-treated pregnant mice.
        Am J Obstet Gynecol. 1997; (In press): 177
        • Mitchell MD
        • Edwin SS
        • Silver RM
        • Romero RJ
        Potential agonist action of the interleukin-1 receptor antagonist protein: implications for treatment of women.
        J Clin Endocrinol Metab. 1993; 76: 1386-1388
        • Colotta F
        • Re F
        • Muzio M
        • Bertini R
        • Polentarutti N
        • Sironi M
        • et al.
        Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4.
        Science. 1993; 261: 472-475
        • Sims JE
        • Gayle MA
        • Slack JL
        • Alderson MR
        • Bird TA
        • et al.
        Interleukin 1 signaling occurs exclusively via the type I receptor.
        Proc Natl Acad Sci U S A. 1993; 90: 6155-6159
        • Wickremasinghe RG
        The role of prostaglandins in the regulation of cell proliferation.
        Prostaglandins Leukotrienes Essent Fatty Acids. 1988; 31: 17117-17119
        • Lee BY
        • Huynh T
        • Prichard LE
        • McGuire J
        • Polan ML
        Gonadal steroids modulate interleukin-1 receptor antagonist mRNA expression in cultured human monocytes.
        Biochem Biophys Res Commun. 1995; 209: 279-285
        • Simon C
        • Frances A
        • Lee BY
        • Mercader A
        • Huynh T
        • Remohi J
        • et al.
        Immunohistochemical localization, identification and regulation of the interleukin-1 receptor antagonist in the human endometrium.
        Hum Reprod. 1995; 10: 2472-2477