INTERLEUKIN-1-BETA INTRAAMNIOTIC INFUSION INDUCES TUMOR-NECROSIS-FACTOR-ALPHA, PROSTAGLANDIN PRODUCTION, AND PRETERM CONTRACTIONS IN PREGNANT RHESUS-MONKEYS

OBJECTIVE: To describe the temporal and quantitative consequences of i ntra-amniotic interleukin-1 beta infusion in a nonhuman primate model. METHODS: On days 128-138 of gestation (term 167 days), four chronical ly instrumented rhesus monkeys (Macaca mulatta) underwent serial intra -amniotic infusions of 2, 5, and 10-20 mu g recombinant human interleu kin-1 beta. Each infusion was for 2 hours, and subsequent infusions we re at least 48 hours later. Amniotic fluid was sampled serially both b efore and after infusion for interleukin-1 beta, tumor necrosis factor -alpha (TFN-alpha), and prostaglandin (PG) E(2) and F-2 alpha by speci fic assays, and uterine activity in each monkey was recorded continuou sly. RESULTS: Intra-amniotic concentrations of interleukin-1 beta rose dramatically after infusion. This rise was rapidly followed by the ap pearance of TNF-alpha in the amniotic cavities of all animals, with ma ximal levels reached 5 hours after the initiation of the infusion. Bot h interleukin-1 beta and TNF-alpha were rapidly cleared from the amnio tic fluid and returned to baseline levels by 24-48 hours. Increases in PGE(2) and F-2 alpha paralleled those of the two cytokines but remain ed elevated for the duration of the experiments. The stimulation of ut erine contractility from a pre-infusion level of 200 mmHg . seconds/ho ur to 6000 mmHg . seconds/hour occurred an average of 6-10 hours after interleukin-1 beta infusion. These stimulations were transient, usual ly abating by 22 hours after infusion, and did not result in frank lab or. CONCLUSION: In the rhesus monkey, intra-amniotic infusion of inter leukin-1 beta rapidly induces production of intra-amniotic TNF-alpha a s well as PGE(2) and F-2 alpha, followed by uterine contractility. Ute rine activity diminishes as cytokine levels return to pre-infusion lev els, even in the presence of elevated intra-amniotic PG levels. Tumor necrosis factor-alpha may act synergistically with interleukin-1 beta in the pathophysiology of cytokine-related preterm labor.