INTERLEUKIN 10 INHIBITS INTERLEUKIN 1? INDUCED PRETERM LABOR IN RHESUS MONKEYS

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Proinflammatory cytokines including interleukin-1? (IL-1?) play a central role in the pathophysiology of infection-induced preterm labor. Interleukin-10 (IL-10), an antiinflammatory cytokine, leads to deactivation of macrophages and inhibits the production of proinflammatory cytokines. We utilized pregnant rhesus monkeys with timed gestations to investigate the hypothesis that IL-10 may inhibit preterm uterine contractions induced by IL-1?. Study Design. Four chronically instrumented pregnant rhesus macaques at 135 days of gestation (term is 167 days) were given intravenous (25 ?g/kg 3 times daily) and intraamniotic (100 ?g 3 times daily) infusions of recombinant IL-10 for three days. After the first dose, animals received intraamniotic infusions of 10 ?g of IL-1? (which we have previously established to reliably stimulate uterine contractility). For comparison, 7 days and 14 days after combined IL-10 and IL-1? infusion, each animal received repeat intraamniot ic i nfusions of IL-1? without IL-10. Uterine contractility (HCA; hourly contraction area), and amniotic fluid (AF) concentrations of IL-1?, IL-10, TNF, prostaglandins E2 (PGE2) and F2? (PGF2?) were serially determined before, during, and after each infusion. Results. Treatment with IL-10 significantly reduced IL-1? induced uterine contractility when administered concurrently with IL-1? (by 85%, *p<0.05), when compared to IL-1? infusion alone 14 days later, when AF IL-10 was no longer detected. Between 0 and 14 days, an inverse relationship was noted between AF IL-10 concentrations and uterine contractility. IL-10 was detected within AF for a minimum of 7 days following IL-10 infusion. The terminal-phase half-life of AF IL-10 was 14 hours. No adverse reactions were noted during IL-10 infusion. Median Peak AF Concentration (ng/ml) Peak Uterine Contractility Event IL-1? IL-10 TNF PGE2 PGF2? (HCA; mmHg?sec/hr) Baseline 0 0 0 0.26 0.15 2600 IL-1? + IL-10 35.3 106.8 460 6.4 0.78 1,800* IL-1? alone + 14d 38.6 0 859 7.7 1.5 11,650 Conclusions. We conclude that IL-10 effectively inhibits IL-1? induced preterm uterine contractility, and may represent a useful adjunct in the treatment of infection-induced preterm labor. FUNDING NIH AI42490, HD06159 PUBLICATIONS Gravett MG, Novy MJ, Haluska GJ, Sadowsky DW, Cook MJ, Witkin SS. Interleukin-10 (IL-10) inhibits interleukin-1? (IL-1?), induced preterm labor in rhesus monkeys. Infect Dis Obstet Gynecol 6:77-78, 1998.