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Effect of Stimulation and Antagonism of Interleukin-1 Signaling on Preterm Delivery in Mice

Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York

Emmet Hirsch, MD

Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York; Department of Obstetrics and Gynecology, Evanston Northwestern Healthcare, 2650 Ridge Ave., Evanston, IL 60201 e-hirsch{at}northwestern.edu

Objective: Transgenic mice that overexpress the interleukin-1 receptor antagonist (IL-1ra), an endogenous competitive inhibitor of interleukin-1 (IL-1) signaling, were used to test whether blockade of IL-1 can prevent bacterially induced preterm delivery in a validated murine model. These IL-1ra transgenic mice have been shown previously to be protected from lethal endotoxin shock.

Methods: In a series of four separate experiments, 201 female wild-type and transgenic mice on day 14.5 of a 19-20 day gestation underwent intrauterine injection with either 0.5-20 µg of recombinant human IL-1ß (rhIL-1ß) or 10⁵-10⁸ heat-killed Escherichia coli organisms. Fetuses were either all wild-type, all transgenic, or of mixed genotype (see below). Preterm delivery and maternal survival rates were recorded. IL-1ra protein levels were determined by enzyme-linked immunosorbent assay (ELISA).

Results: Intrauterine administration of IL-1ß induced preterm delivery in a dose-dependent manner and did not cause other adverse maternal effects. In bacterially inoculated mice, neither maternal nor fetal carriage of the IL-1ra overrexpression transgene affected preterm delivery rates. Fetal carriage of the IL-1ra transgene did not up-regulate IL-1ra protein levels in maternal or fetal tissues.

Conclusion: Although intrauterine IL-1 exposure is sufficient for induction of preterm delivery, it was not possible to prevent bacterially induced preterm birth using the IL-1ra transgene. This may be either because the timing or magnitude of IL-1ra up-regulation in transgenic mice was insufficient to block IL-1's interaction with its receptor, or because bacterially induced laboar in this model does not depend on IL-1 signaling alone.

Key Words: Interleukin-1 • IL-1 receptor antagonist • preterm delivery • intrauterine infection

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