TRANSFORMING GROWTH-FACTOR-BETA-2 PREVENTS PRETERM DELIVERY INDUCED BY INTERLEUKIN-1-ALPHA AND TUMOR-NECROSIS-FACTOR-ALPHA IN THE RABBIT

OBJECTIVES: The purpose of the study was to determine whether preterm parturition in the rabbit can be induced by intraamniotic injection of proinflammatory cytokines, interleukin-1alpha and tumor necrosis factor-alpha, and whether transforming growth factor-beta2, an inhibitor of the cytokine-induced prostaglandin synthesis, modifies the effect of these cytokines. STUDY DESIGN: New Zealand White rabbits were injected in each amniotic cavity on day 24 of gestation with one of the following: a combination of interleukin-1alpha (150 ng) and tumor necrosis factor-alpha (1.25 mug), 50 ng of transforming growth factor-beta2 concomitantly with interleukin-1alpha and tumor necrosis factor-alpha, or vehicle. In the first study the animals were observed for signs of delivery until day 29 of gestation. In the second study the effect of transforming growth factor-beta2 (50 ng/fetus) on the rate of premature delivery was evaluated. In the third study the concentrations of prostaglandin E2 and 13,14-dihydro-15-keto-prostaglandin F2alpha were measured in the amniotic fluid on day 27 of gestation. The statistics used were Fisher's exact test, the chi2 test, and the Mann-Whitney U test. RESULTS: Altogether 61 of 191 fetuses (32%) were born prematurely in the interleukin-1alpha-tumor necrosis factor-alpha group, whereas only two of 161 fetuses (1.2%) (p = 0.0001) and one of 159 (0.6%) (p = 0.0001) were born prematurely in the interleukin-1alpha-tumor necrosis factor-alpha-transforming growth factor-beta2 group and in the control group, respectively. Of the 23 animals injected with interleukin-1alpha and tumor necrosis factor-alpha, six (26%) delivered all of their fetuses prematurely versus none in the other groups (p = 0.02). None of the 88 fetuses in the transforming growth factor-beta2 group were born prematurely. The prostaglandin E2 concentrations in the amniotic fluids were higher in the interleukin-1alpha-tumor necrosis factor-alpha group than in the interleukin-1alpha-tumor necrosis factor-alpha-transforming growth factor-beta2 group (p = 0.05) or in the control group (p = 0.02). CONCLUSIONS: Preterm parturition can be provoked in the rabbit by intraamniotic injections of interleukin-1alpha and tumor necrosis factor-alpha. Transforming growth factor-beta2 prevents the cytokine-induced increase in premature delivery.