Inflammatory cytokines in a murine model of infection-induced preterm labor: cause or effect?

J Soc Gynecol Investig. Jul-Aug 1999;6(4):188-95. doi: 10.1016/s1071-5576(99)00013-1.

Abstract

Objective: To characterize the expression of inflammatory cytokines in a murine model of preterm delivery induced by heat-killed bacteria.

Methods: The right uterine horns of female CD-1 mice on day 14.5 of 19-20 days of gestation were inoculated with either sterile media or killed Escherichia coli bacteria (10(5)-10(10) organisms per mouse). The incidence of preterm delivery was recorded. The concentrations of cytokines (interleukin [IL-] 1 alpha, IL-1 beta, IL-1 receptor antagonist [IL-1ra], IL-6, and tumor necrosis factor alpha [TNF alpha]) within maternal and fetal tissue homogenates were determined by enzyme-linked immunosorbent assay at various times after inoculation.

Results: Killed E. coli induced preterm delivery in a dose-dependent fashion. Inoculation with 10(10) bacteria (sufficient to cause delivery in all mice) produced increases in IL-1 alpha, IL-1 beta, IL-6, and TNF alpha within uteri and fetal membranes, but not within placentas, fetal bodies, and maternal serum. Maximum mean uterine levels of IL-1 and IL-6 exceeded those of fetal tissues (membranes, placentas, and fetal bodies) by greater than 15-fold. Maximal uterine IL-1 and TNF alpha levels following inoculation with 10(10) bacteria exceeded those that followed inoculation with 10(7) bacteria (below the threshold for delivery) by 2.5- to 5-fold. The anti-inflammatory cytokine IL-1ra was expressed in higher concentrations in fetal than in maternal tissues and was unaltered by the bacterial inoculum.

Conclusions: E. coli induce labor in mice even in the absence of bacterial viability. Although IL-1 and TNF alpha were upregulated by bacterial inocula causing delivery, peak levels were only 2.5- to 5-fold higher than those that occurred with inocula below the threshold for delivery (1000-fold fewer bacteria). Whether IL-1 and TNF alpha mediate labor during in vivo infection, or whether the upregulation of these cytokines merely represents an epiphenomenon accompanying infection, remains unknown.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bacterial Toxins / pharmacology
  • Cytokines / blood
  • Cytokines / metabolism*
  • Disease Models, Animal*
  • Enzyme-Linked Immunosorbent Assay
  • Escherichia coli / pathogenicity
  • Extraembryonic Membranes / drug effects
  • Extraembryonic Membranes / metabolism
  • Female
  • Fetus / drug effects
  • Fetus / metabolism
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukins / blood
  • Interleukins / metabolism
  • Male
  • Mice
  • Obstetric Labor, Premature / metabolism
  • Obstetric Labor, Premature / microbiology*
  • Placenta / drug effects
  • Placenta / metabolism
  • Pregnancy
  • Pregnancy Complications, Infectious / metabolism
  • Pregnancy Complications, Infectious / microbiology
  • Sialoglycoproteins / blood
  • Sialoglycoproteins / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism
  • Uterus / drug effects
  • Uterus / metabolism
  • Uterus / pathology

Substances

  • Bacterial Toxins
  • Cytokines
  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukins
  • Sialoglycoproteins
  • Tumor Necrosis Factor-alpha