Systemic administration of interleukin-l induces preterm parturition in mice Roberto Romero, MD,. Moshe Mazor, MD," and Boris Tartakovsky, PhD' Nl'w Haven, Connecticut, and B eer Sheva and Rehovot, Israel Interleukin-1 has been postulated as a signal for the initiation of preterm labor and delivery. Interleukin-1 is produced by human decidua, stimulates prostaglandin production by intrauterine tissues, and is present in the amniotic fluid of women with preterm labor and intraamniotic infection. The purpose of these studies was to determine whether interleukin-1 could induce parturition in an animal species. Timed-pregnant C3H/HeJ inbred mice (n = 24) (genetically endotoxin resistant) were randomized to receive either recombinant human interleukin-1 or sterile phosphate-buffered saline solution between days 15 and 17 of gestation (normal length of pregnancy, 20 to 21 days). Three consecutive subcutaneous injections of interleukin-1 or phosphate-buffered saline solution were administered within 6 hours. Examinations of the animals were performed by blinded observers. Parturition occurred within 24 hours in all of the interleukin-1-treated mice and in none of the control group. Vaginal bleeding was first noted 4 hours after the first interleukin-1 injection, and delivery began within 12 hours after the last interleukin-1 injection. Premature delivery occurred in all interleukin-1-injected mice. Laparotomy revealed that there were no remaining fetuses in utero. All mice in the control group delivered spontaneously between days 20 and 22. We conclude that systemic administration of interleukin-1 induces preterm labor and delivery in mice. (AM J OBSTET GVNECOL 1991;165:969-71.)
Key words: Interleukin-l, cytokines, parturition, labor, chorioamnionitis, prematurity, preterm labor, mice There is a strong assoCIatIon between systemic or intrauterine infection and preterm labor and delivery (reviewed in reference I). It has been estimated that at least 20% of preterm births occur in women with microbial invasion of the amniotic cavity! However, the mechanisms responsible for the initiation of parturition in the setting of infection have not been elucidated. Interleukin-l (IL-I), a cytokine produced by human decidua in response to bacterial products,' has been proposed as a signal for the initiation of labor in the setting of infection.' Although IL-I stimulates prostaglandin production by human amnionS and decidua" and is present in the amniotic fluid of women with preterm labor and microbial invasion of the amniotic cavity, there is no direct evidence that this cytokine can induce parturition" The purpose of these studies was to determine whether systemic administration of IL-l can induce parturition in mice.
From the Department of Obstetrics and Gynecology, Yale University School of Medicine," Sorolw Medical Center,' and the Department of Chemical Immunology, The Weizmann Institute of Science.' Supported by a grant from the Walter Scott Foundation for Medical R esearch. Dr. Romero is supported by a Physician Scientist Award fmm the Nationalinstitute of Child H ealth and Human Development. Presented at the Eleventh Annual M eeting of the Society of Perinatal Obstetricians, San Francisco, California, Janua1J 28-Feb1·uary 2,
1991 .
Reprint requests: Roberto Romero, MD, Department of Obstetrics and Gynecology, 333 Cedar St. , P.O. Box 3333, New Haven, CT06510. 6/6/30936
Material and methods Animals. Mice were selected as the experimental animal because of the investigators' familiarity with murine reproductive biology and the considerable information available regarding the immune system and cytokine physiology in this species. Studies were conducted with 19-week-old C3H / HeJ mice that were impregnated by C57BLl6J X DBA/2 F-l male mice. Animals were allowed free access to food and water before and during experimentation and were exposed to a 12-hour-lightI12-hour-dark cycle. Under these conditions mating occurs during the mid-dark period. Mating date, as evidenced by vaginal plug, was designated day 1 of pregnancy. Experimental design. Twenty-four mice were randomized to receive human recombinant IL-la (Hazelton Laboratories, Baltimore) (n = 12) or sterile phosphate-buffered saline solution (n = 12) subcutaneously. Gestational ages were 15 days (n = 12), 16 days (n = 4), and 17 days (n = 8). Normal duration of pregnancy in this mating combination is 20 to 21 days. Randomization was stratified for gestational age. Injections consisted of 1 fLg of IL-Ia diluted in 100 fLl of sterile phosphate-buffered saline solution or 100 fLl of phosphate-buffered saline solution. The endotoxin content of this preparation of IL-Ia is
Key words: Interleukin-l, cytokines, parturition, labor, chorioamnionitis, prematurity, preterm labor, mice There is a strong assoCIatIon between systemic or intrauterine infection and preterm labor and delivery (reviewed in reference I). It has been estimated that at least 20% of preterm births occur in women with microbial invasion of the amniotic cavity! However, the mechanisms responsible for the initiation of parturition in the setting of infection have not been elucidated. Interleukin-l (IL-I), a cytokine produced by human decidua in response to bacterial products,' has been proposed as a signal for the initiation of labor in the setting of infection.' Although IL-I stimulates prostaglandin production by human amnionS and decidua" and is present in the amniotic fluid of women with preterm labor and microbial invasion of the amniotic cavity, there is no direct evidence that this cytokine can induce parturition" The purpose of these studies was to determine whether systemic administration of IL-l can induce parturition in mice.
From the Department of Obstetrics and Gynecology, Yale University School of Medicine," Sorolw Medical Center,' and the Department of Chemical Immunology, The Weizmann Institute of Science.' Supported by a grant from the Walter Scott Foundation for Medical R esearch. Dr. Romero is supported by a Physician Scientist Award fmm the Nationalinstitute of Child H ealth and Human Development. Presented at the Eleventh Annual M eeting of the Society of Perinatal Obstetricians, San Francisco, California, Janua1J 28-Feb1·uary 2,
1991 .
Reprint requests: Roberto Romero, MD, Department of Obstetrics and Gynecology, 333 Cedar St. , P.O. Box 3333, New Haven, CT06510. 6/6/30936
Material and methods Animals. Mice were selected as the experimental animal because of the investigators' familiarity with murine reproductive biology and the considerable information available regarding the immune system and cytokine physiology in this species. Studies were conducted with 19-week-old C3H / HeJ mice that were impregnated by C57BLl6J X DBA/2 F-l male mice. Animals were allowed free access to food and water before and during experimentation and were exposed to a 12-hour-lightI12-hour-dark cycle. Under these conditions mating occurs during the mid-dark period. Mating date, as evidenced by vaginal plug, was designated day 1 of pregnancy. Experimental design. Twenty-four mice were randomized to receive human recombinant IL-la (Hazelton Laboratories, Baltimore) (n = 12) or sterile phosphate-buffered saline solution (n = 12) subcutaneously. Gestational ages were 15 days (n = 12), 16 days (n = 4), and 17 days (n = 8). Normal duration of pregnancy in this mating combination is 20 to 21 days. Randomization was stratified for gestational age. Injections consisted of 1 fLg of IL-Ia diluted in 100 fLl of sterile phosphate-buffered saline solution or 100 fLl of phosphate-buffered saline solution. The endotoxin content of this preparation of IL-Ia is
