Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model

Drew W Sadowsky, Kristina M Adams, Michael G Gravett, Steven S Witkin, Miles J Novy
American Journal of Obstetrics and Gynecology 2006, 195 (6): 1578-89

OBJECTIVES: The purpose of this study was to determine the relative contributions of individual proinflammatory cytokines and chemokines to the triggering of preterm labor.

STUDY DESIGN: Eighteen chronically instrumented pregnant rhesus monkeys at 135 +/- 3 days gestation (term = 167 days) received 1 of 5 intraamniotic infusions: (1) interleukin-1beta (IL-1beta) (10 microg; n = 5), (2) tumor necrosis factor-alpha (TNF-alpha) (10-100 microg; n = 5), (3) IL-6 (20 microg twice a day; n = 2), (4) IL-8 (20 microg twice a day; n = 2), and (5) saline control (n = 4). Primary study outcomes were the mean uterine hourly contraction area (mm Hg x s/h) in 24 hours during peak response to cytokine infusion (all groups) and the interval from cytokine infusion until labor onset (IL-1beta, IL-6, and IL-8 groups). Secondary outcomes were quantities of amniotic fluid cytokines and chemokines (IL-1beta, TNF-alpha, IL-6, and IL-8), prostaglandins E2 and F2alpha, leukocytes, and matrix metalloproteinase-9 (MMP-9). Histopathology of fetal lungs and placental membranes was assessed.

RESULTS: IL-1beta stimulated the most intense contraction patterns, resulting in preterm labor in all cases. TNF-alpha induced a variable degree of uterine activity among individual animals stimulating either preterm labor (n = 2) or a uterine contraction pattern of moderate intensity (n = 3). Despite prolonged elevations in amniotic fluid levels, neither IL-6 nor IL-8 induced preterm labor or an increase in uterine activity until near term. The mean interval from the initiation of IL-6 and IL-8 infusion to the onset of labor was significantly longer than after IL-1beta (21.9 vs 1.1 days; P < .01), and did not differ from the saline control group (27.6 days; P = NS). Intraamniotic infusion of IL-1beta or TNF-alpha was associated with significant elevations in all tested amniotic fluid cytokines, IL-8, prostaglandins, MMP-9 and leukocytes compared with gestational age-matched saline controls. IL-6 and IL-8 infusions were not associated with increases in IL-1beta or TNF-alpha and only produced a moderate increase in amniotic fluid prostaglandins. All cytokine infusions induced histologic chorioamnionitis and an accumulation of neutrophils in fetal lungs.

CONCLUSION: Preterm labor was induced by intraamniotic infusions of IL-1beta and TNF-alpha, but not by IL-6 or IL-8 although inflammatory changes in fetal membranes and lungs were uniformly present. Our results indicate a primary role for IL-1beta and TNF-alpha in the triggering of preterm labor associated with inflammation or infection.

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