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


METHODS
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.


CONCLUSIONS
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.
Sadowsky
Drew W
DW
Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR, USA.
Adams
Kristina M
KM
Gravett
Michael G
MG
Witkin
Steven S
SS
Novy
Miles J
MJ
D000653:Amniotic Fluid / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002821:Chorioamnionitis / Q000139:chemically induced; D016207:Cytokines / Q000378:metabolism; D005321:Extraembryonic Membranes / Q000187:drug effects / Q000473:pathology; D005260:Female; D005865:Gestational Age; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007267:Injections; D053583:Interleukin-1beta / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology; D016209:Interleukin-8 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D008253:Macaca mulatta; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020556:Neutrophil Infiltration; D007752:Obstetric Labor, Premature / Q000139:chemically induced*; D011247:Pregnancy; D011453:Prostaglandins / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D014590:Uterine Contraction; D014599:Uterus / Q000187:drug effects
D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D011453:Prostaglandins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9