Effect of stimulation and antagonism of interleukin-1 signaling on preterm delivery in mice.
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 microg of recombinant human IL-1beta (rhIL-1beta) or 10(5)-10(8) 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-1beta 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 overexpression 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.


CONCLUSIONS
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 labor in this model does not depend on IL-1 signaling alone.
Yoshimura
Kazuaki
K
Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Hirsch
Emmet
E
D000818:Animals; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000150:complications; D005260:Female; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction
D007375:Interleukin-1; D017472:Receptors, Interleukin-1