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

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 I of 5 intraamniotic infusions: (1) interleukin-1 beta (IL-1 beta) (10 mu g; n = 5), (2) tumor necrosis factor-alpha (TNF-alpha) (10-100 mu g; n = 5), (3) IL-6 (20 mu g twice a day; n = 2), (4) IL-8 (20 mu g 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-1 beta, IL-6, and IL-8 groups). Secondary outcomes were quantities of amniotic fluid cytokines and chemokines (IL-1 beta, TNF-alpha, IL-6, and IL-8), prostaglandins E-2 and F-2 alpha leukocytes, and matrix metal-loprotemase-9 (MMP-9). Histopathology of fetal lungs and placental membranes was assessed. Results: IL-1 beta stimulated the most intense contraction patterns, resulting in preterm labor in all cases. TNF-a 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-1 beta (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-1 beta 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-1 beta or TNF-alpha and only produced a moderate increase in amnotic 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-1 beta 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-1 beta and TNF-alpha in the triggering of preterm labor associated with inflammation or infection. (c) 2006 Mosby, Inc. All rights reserved.