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Treatment With the Interleukin-1 Receptor Antagonist and Soluble Tumor Necrosis Factor Receptor Fc Fusion Protein Does Not Prevent Endotoxin-Induced Preterm Parturition in Mice

Departments of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan; the Perinatology Research Branch, National Institutes of Child Health and Human Development, Bethesda, Maryland; Departments of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul, Korea; Department of Microbiology, Immunology, and Parasitology, Louisiana State University Medical Center, New Orleans, LA 70112

Robert Romero, MD

Jessic Cutright, BS

Norbert Wolf, MT

Ricardo Gomez, MD

Heriberto Araneda, MT

Marcelo Ramirez, MT

Bo Hyun Yoon, MD, PhD

Departments of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan; Perinatology Research Branch, National Institutes of Child Health and Human Development, Bethesda, Maryland; Departments of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul, Korea

Objective: To determine whether the administration of anticytokine agents, the interleukin-1 receptor antagonist (IL-1ra) and a soluble tumor necrosis factor receptor Fc fusion protein (sTNFR-Fc), prevents endotoxin-induced preterm delivery in mice.

Methods: C3H/HeN pregnant mice at 15 days of gestation (70% gestation) were randomized to receive phosphate-buffered saline (PBS) or lipopolysaccharide (LPS) (50 µg/mouse) intraperitoneally (i.p.). Randomly selected PBS- or LPS-treated mice were additionally treated intravenously (i.v.), i.p., or subcutaneously (s.c.) every 3 hours with IL-1ra (1-50 mg) or every 12 hours with sTNFR-Fc (200-400 µg) beginning 1 hour before LPS injection. Animals were observed for vaginal bleeding and preterm delivery.

Results: Mice treated i.p. with 50 µg LPS (n = 13) had a shorter injection-to-delivery interval than mice treated similarly with PBS (n = 19) (median 13.5 hours, range 10-105 versus median 86.8 hours, range 53-120, respectively; P < .001) Saline-treated mice given 10 mg IL-1ra every 3 hours i.p. (n = 3) or 200 µg sTNFR-Fc every 12 hours i.v. (n = 4) had similar injection-to-delivery intervals as PBS-treated control mice (median 70 hours, range 70-76 versus median 58 hours, range 50-120, respectively). Similarly, LPS-treated mice given PBS every 3 hours (n = 20) had injection-to-delivery intervals comparable to LPS-treated mice (n = 13) (median 15.5 hours, range 9.8-92 versus median 13.5 hours, range 10-105, respectively). Lipopolysaccharide-treated mice given i.p. injections of 1 (n = 4), 10 (n = 31), or 50 (n = 15) mg of IL-1ra every 3 hours did not have longer injection-to-delivery intervals compared with LPS-treated mice (n = 13) (medians 11.6, 15, 14.5, and 13.5 hours; ranges 10.8-12, 8-95, 11-92, and 10-105, respectively). Lipopolysaccharide-treated mice given i.v. injections of 200 (n = 4) or 400 (n = 9) µg sTNFR-Fc every 12 hours did not have longer injection-to-delivery intervals compared with LPS-treated mice (n = 8) (medians 23.3, 22.5, and 21.9 hours; ranges 14.8-33, 15-95.5, and 15.5-44, respectively). The median injection-to-delivery interval of LPS-treated mice given both IL-1ra (10 mg) every 3 hours i.p. and sTNFR-Fc (200 µg) every 12 hours i.v. (n = 5) was not different from that of LPS-treated mice (median 26 hours, range 24.5-72 versus median 13.5 hours, range 10-105; respectively; P > .05).

Conclusions: The anticytokine agents IL-1ra and sTNFR-Fc did not did not prevent preterm delivery or prolong pregnancy in endotoxin-induced preterm labor in mice.

Key Words: Preterm parturition • endotoxin • murine model • interleukin-1 receptor antagonist • soluble tumor necrosis factor receptor Fc fusion protein

Journal of the Society for Gynecologic Investigation, Vol. 4, No. 1, 22-26 (1997)
DOI: 10.1177/107155769700400104


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