Pretreatment With Toll-like Receptor 4 Antagonist Inhibits Lipopolysaccharide-Induced Preterm Uterine Contractility, Cytokines, and Prostaglandins in Rhesus Monkeys

Intrauterine infection, which occurs in most early preterm births, triggers an immune response culminat-ing in preterm labor. The authors hypothesize that blockade of lipopolysaccharide (LPS)–induced immune responses by a toll-like receptor 4 antagonist (TLR4A) would prevent elevations in amniotic fluid (AF) cytokines, prostaglandins, and uterine contractility. Chronically catheterized rhesus monkeys at 128 to 147 days ’ gestation received intra-amniotic infusions of either (1) saline (n = 6), (2) LPS (0.15-10 μg; n = 4), or (3) TLR4A pretreatment with LPS (10 μg) 1 hour later (n = 4). AF cytokines, prostaglandins, and uterine contractility were compared using 1-way ANOVA with Bonferroni-adjusted pairwise comparisons. Compared with saline controls, LPS induced significant elevations in AF interleukin-8 (IL-8), tumor necrosis factor (TNF)–α, PGE2, PGF2α, and uterine contractility (P <.05). In contrast, TLR4A pretreatment inhibited LPS-induced uterine activity and was associated with sig-nificantly lower AF IL-8, TNF-α, PGE2, and PGF2α versus LPS alone (P <.05). Toll-like receptor antagonists, together with antibiotics, may delay or prevent infection-associated preterm birth. KEY WORDS: toll-like receptor 4, intrauterine infection/inflammation, preterm labor, rhesus monkey, animal model. We previously demonstrated that immunomodulator