Interleukin-1 beta intra-amniotic infusion induces tumor necrosis factor-alpha, prostaglandin production, and preterm contractions in pregnant rhesus monkeys.
OBJECTIVE
To describe the temporal and quantitative consequences of intra-amniotic interleukin-1 beta 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 micrograms recombinant human interleukin-1 beta. 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-1 beta, tumor necrosis factor-alpha (TFN-alpha), and prostaglandin (PG) E2 and F2 alpha by specific assays, and uterine activity in each monkey was recorded continuously.


RESULTS
Intra-amniotic concentrations of interleukin-1 beta rose dramatically after infusion. This rise was rapidly followed by the appearance of TNF-alpha in the amniotic cavities of all animals, with maximal levels reached 5 hours after the initiation of the infusion. Both interleukin-1 beta and TNF-alpha were rapidly cleared from the amniotic fluid and returned to baseline levels by 24-48 hours. Increases in PGE2 and F2 alpha 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-1 beta infusion. These stimulations were transient, usually abating by 22 hours after infusion, and did not result in frank labor.


CONCLUSIONS
In the rhesus monkey, intra-amniotic infusion of interleukin-1 beta rapidly induces production of intra-amniotic TNF-alpha as well as PGE2 and F2 alpha, followed by uterine contractility. Uterine activity diminishes as cytokine levels return to pre-infusion levels, even in the presence of elevated intraamniotic PG levels. Tumor necrosis factor-alpha may act synergistically with interleukin-1 beta in the pathophysiology of cytokine-related preterm labor.
Baggia
S
S
Division of Reproductive Sciences, Oregon Regional Primate Research Center, Beaverton 97006, USA.
Gravett
M G
MG
Witkin
S S
SS
Haluska
G J
GJ
Novy
M J
MJ
D000653:Amniotic Fluid; D000818:Animals; D015237:Dinoprost / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D008253:Macaca mulatta; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects / Q000502:physiology*; D011453:Prostaglandins / Q000032:analysis / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects / Q000502:physiology
D007375:Interleukin-1; D011453:Prostaglandins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015237:Dinoprost; D015232:Dinoprostone