Objective:To describe the temporal and quantitative consequences of intra-amniotic interleukin-1β infusion in a nonhuman primate model.
Methods:On days 128-138 of gestation (term 167 days), four chronically instrumented rhesus monkeys (Macaca mulatta) underwent serial intra-amniotic infusions of 2, 5, and 10-20 μg recombinant human interleukin-1β. Each infusion was for 2 hours, and subsequent infusions were at least 48 hours later. Amniotic fluid was sampled serially both before and after infusion for interleukin-1β, tumor necrosis factor-α (TFN-α), and prostaglandin (PG) E2 and F2α by specific assays, and uterine activity in each monkey was recorded continuously.
Results:Intra-amniotic concentrations of interleukin-1β rose dramatically after infusion. This rise was rapidly followed by the appearance of TNF-α in the amniotic cavities of all animals, with maximal levels reached 5 hours after the initiation of the infusion. Both interleukin-1β and TNF-α were rapidly cleared from the amniotic fluid and returned to baseline levels by 24-48 hours. Increases in PGE2 and F2α paralleled those of the two cytokines but remained elevated for the duration of the experiments. The stimulation of uterine contractility from a pre-infusion level of 200 mmHg · seconds/hour to 6000 mmHg · seconds/hour occurred an average of 6-10 hours after interleukin-1β infusion. These stimulations were transient, usually abating by 22 hours after infusion, and did not result in frank labor.
Conclusion:In the rhesus monkey, intra-amniotic infusion of interleukin-1β rapidly induces production of intra-amniotic TNF-α as well as PGE2 and F2α, followed by uterine contractility. Uterine activity diminishes as cytokine levels return to pre-infusion levels, even in the presence of elevated intra-amniotic PG levels. Tumor necrosis factor-α may act synergistically with interleukin-1β in the pathophysiology of cytokine-related preterm labor.
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