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Interleukin-Iß Intra-Amniotic Infusion Induces TUmor Necrosis Factor-, Prostaglandin Production, and Preterm COntractions in Pregnant Rhesus Monkeys

Michael G. Gravett, MD

Steven S. Witkin, PhD

George J. Haluska, PhD

Miles J. Novy, MD

Division of Reproductive Sciences, Oregon Regional Primate Research Center, Beaverton, Oregon; Department of Obstetrics and GYnecology, Legacy Emanual Hospital and Health Center, Portland, Oregon; Department of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, Oregon; Department of Obstetrics and Gynecology, Cornell University Medical College, New York, New York

Objective: To describe the temporal and quantitative consequences of intra-amniotic interleukin-1ß 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-1ß. 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-1ß, tumor necrosis factor- (TFN-), and prostaglandin (PG) E₂ and F₂ by specific assays, and uterine activity in each monkey was recorded continuously.

Results: Intra-amniotic concentrations of interleukin-1ß rose dramatically after infusion. This rise was rapidly followed by the appearance of TNF- in the amniotic cavities of all animals, with maximal levels reached 5 hours after the initiation of the infusion. Both interleukin-1ß and TNF- were rapidly cleared from the amniotic fluid and returned to baseline levels by 24-48 hours. Increases in PGE₂ and F₂ 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-1ß 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-1ß rapidly induces production of intra-amniotic TNF- as well as PGE₂ and F₂, 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- may act synergistically with interleukin-1ß in the pathophysiology of cytokine-related preterm labor.

Key Words: Interleukin-1ß • tumor necrosis factor- • prostaglandin • preterm labor • rhesus monkey

Journal of the Society for Gynecologic Investigation, Vol. 3, No. 3, 121-126 (1996)
DOI: 10.1177/107155769600300304


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