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 culminating 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 microg; n = 4), or (3) TLR4A pretreatment with LPS (10 microg) 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)- alpha, PGE(2), PGF(2)(alpha), and uterine contractility (P < .05). In contrast, TLR4A pretreatment inhibited LPS-induced uterine activity and was associated with significantly lower AF IL-8, TNF-alpha, PGE(2), and PGF(2)( alpha) versus LPS alone (P < .05). Toll-like receptor antagonists, together with antibiotics, may delay or prevent infection-associated preterm birth.
Adams Waldorf
Kristina M
KM
University of Washington, Seattle, WA 98195, USA. adamsk@u.washington.edu
Persing
David
D
Novy
Miles J
MJ
Sadowsky
Drew W
DW
Gravett
Michael G
MG
D000653:Amniotic Fluid / Q000382:microbiology; D000818:Animals; D002821:Chorioamnionitis; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004926:Escherichia coli; D005260:Female; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology*; D008253:Macaca mulatta; D007752:Obstetric Labor, Premature / Q000276:immunology* / Q000517:prevention & control; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology*; D011453:Prostaglandins / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D014590:Uterine Contraction / Q000187:drug effects* / Q000276:immunology; D014591:Uterine Diseases / Q000382:microbiology
D016207:Cytokines; D008070:Lipopolysaccharides; D011453:Prostaglandins; D051197:Toll-Like Receptor 4