Dexamethasone or interleukin-10 blocks interleukin-1beta-induced uterine contractions in pregnant rhesus monkeys.
OBJECTIVE
The purpose of this study was to determine whether treatment with the immune modulators dexamethasone or interleukin-10 prevents interleukin-1beta-induced uterine contractions in a nonhuman primate model.


METHODS
Thirteen chronically instrumented rhesus monkeys at 135 +/- 1 days of gestation (term, 167 days) received one of three interventions: (1) intra-amniotic interleukin-1beta (10 microg) infusion with maternal dexamethasone (1 mg/kg) intravenously every 6 hours for 1 day before interleukin-1beta and for 2 days thereafter (n = 4), (2) intra-amniotic interleukin-1beta infusion with maternal interleukin-10 (25 microg/kg) given intravenously and 100 microg interleukin-10 given intra-amniotically before the interleukin-1beta and continued every 8 hours for 3 days (n = 5), and (3) intra-amniotic interleukin-1beta administered alone (n = 5). Uterine activity was monitored continuously and quantified as the hourly contraction area (millimeters of mercury times seconds per hour) in all groups until delivery. Amniotic fluid was sampled for leukocyte counts and assayed for prostaglandins E(2) and F(2)alpha, cytokines interleukin-1beta, interleukin-6, interleukin-8, tumor necrosis factor-alpha, interleukin-10, and interleukin-1 receptor antagonist by specific assays. Maternal and fetal blood were assayed for cortisol, dehydroepiandrosterone sulfate, and estradiol.


RESULTS
Interleukin-1beta infusion in the absence of immune modulators resulted in an increase in uterine activity and amniotic fluid proinflammatory cytokines, prostaglandins, and leukocytes. Dexamethasone and interleukin-10 treatment significantly reduced interleukin-1beta-induced uterine contractility (P <.05) and amniotic fluid prostaglandins (P <.05) but not interleukin-8 or interleukin-1 receptor antagonist. Amniotic fluid interleukin-6 and maternal and fetal cortisol, dehydroepiandrosterone sulfate, and estradiol concentrations were reduced by dexamethasone (P <.05), whereas tumor necrosis factor-alpha levels and leukocyte counts were attenuated by interleukin-10 treatment (P <.05). An inverse relationship was noted between amniotic fluid interleukin-10 concentrations and interleukin-1beta-induced uterine activity (r = -0.74, P <.05).


CONCLUSIONS
Dexamethasone and interleukin-10 exert similar inhibitory effects on interleukin-1beta-induced uterine activity, which appears to be mediated by a decrease in prostaglandin production. Reduced estrogen biosynthesis or suppression of tumor necrosis factor-alpha and leukocyte migration may contribute to the tocolytic actions of dexamethasone and interleukin-10, respectively. Dexamethasone and interleukin-10 are likely to be useful adjuncts in the treatment of preterm labor that is associated with inflammation or infection.
Sadowsky
Drew W
DW
Division of Reproductive Sciences, Oregon Regional Primate Research Center, Oregon Health Sciences University, Portland, OR 97201, USA.
Novy
Miles J
MJ
Witkin
Steven S
SS
Gravett
Michael G
MG
D000653:Amniotic Fluid / Q000737:chemistry / Q000166:cytology; D000818:Animals; D016207:Cytokines / Q000032:analysis; D003907:Dexamethasone / Q000494:pharmacology*; D015237:Dinoprost / Q000032:analysis; D015232:Dinoprostone / Q000032:analysis; D004347:Drug Interactions; D005260:Female; D005865:Gestational Age; D005938:Glucocorticoids / Q000494:pharmacology*; D006340:Heart Rate, Fetal; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D007958:Leukocyte Count; D008253:Macaca mulatta; D011247:Pregnancy; D011453:Prostaglandins / Q000032:analysis; D012795:Sialoglycoproteins / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014590:Uterine Contraction / Q000187:drug effects*
D016207:Cytokines; D005938:Glucocorticoids; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D011453:Prostaglandins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D003907:Dexamethasone; D015237:Dinoprost; D015232:Dinoprostone