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

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.