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Inflammatory Cytokines in a Murine Model of Infection-Induced Preterm Labor: Cause or Effect?

Ryan Blanchard, BS

Steven R. Brunnert, DVM

Department of Obstetrics and Gynecology and The Institute for Comparative Medicine, Columbia University College of Physicians and Surgeons, New York, New York

Emmet Hirsch, MD

Department of Obstetrics and Gynecology and The Institute for Comparative Medicine, Columbia University College of Physicians and Surgeons, New York, New York; eh25{at}columbia.edu

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 Excherichia coli bacteria (10⁵-10¹⁰ organisms per mouse). The incidence of preterm delivery was recorded. The concentrations of cytokines (itnerleukin [IL-] 1, IL-1ß, IL-1 receptor antagonist [IL-1ra], IL-6, and tumor necrosis factor [TNF]) 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 10¹⁰ bacteria (sufficient to cause delivery in all mice) produced increases in IL-1, IL-1ß, IL-6, and TNF 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 levels following inoculation with 10¹⁰ bacteria exceeded those that followed inoculation with 10⁷ 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 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 mediate labor during in vivo infection, or whether the upregulation of these cytokines merely represents an epiphenomenon accompanying infection, remains unknown.

Key Words: Infection • pregnancy • mouse • cytokines • killed bacteria • animal model

Journal of the Society for Gynecologic Investigation, Vol. 6, No. 4, 188-195 (1999)
DOI: 10.1177/107155769900600405


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