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

      Abstract

      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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