title: Inflammatory cytokines in a murine model of infection-induced preterm labor: cause or effect?
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.
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Mussalli
authors.forename: R
authors.initials: R
authors.lastname: Blanchard
authors.forename: S R
authors.initials: SR
authors.lastname: Brunnert
authors.forename: E
authors.initials: E
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000472:pathogenicity; D005321:Extraembryonic Membranes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D007752:Obstetric Labor, Premature / Q000378:metabolism / Q000382:microbiology*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000378:metabolism / Q000382:microbiology; D012795:Sialoglycoproteins / Q000097:blood / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D001427:Bacterial Toxins; D016207:Cytokines; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha