More than 200,000 premature infants are born every year in this country. These infants are at risk for death, major neonatal morbidity and long term mental and neurologic handicap. The human and economic cost of premature labor to society makes it an urgent health care priority. The mechanisms responsible for its onset are poorly understood. Despite major clinical efforts, the successful treatment of this complication remains a medical challenge. Previous studies have focused on the mechanisms of normal human labor. Virtually no effort has been devoted to understanding the mechanisms underlying pathologic labor. Premature labor is frequently associated with systemic and intrauterine infections. Histologic studies support a role for inflammation of infectious and non-infectious origin in triggering preterm labor. The objective of our studies is to elucidate the mechanisms underlying the onset of premature labor associated with inflammation of infectious origin in reproductive tissues (decidua, placenta, chorioamnion) and the fetus. Interleukin-1 (IL-1) is a polypeptide hormone produced by phagocytic cells in response to microorganisms. IL-1 induces prostaglandin (PG) release from several cell lines. PGs are established mediators of human parturition. IL-1 is also the mediator of fever. Maternal fever is associated with preterm labor. We therefore postulate that IL-1 of maternal or fetal origin is a signal for the onset of human parturition associated with infection. We will determine the sources and ascertain the effects of IL-1 and its microbial inducers on prostaglandin production in reproductive tissues. We will: 1) physically characterize IL-1-like activity in amniotic fluid and decidua; 2) describe the kinetics and cellular sources of IL-1-like activity in decidua; 3) determine the sources of amniotic fluid IL-1; 4) determine the effect of labor and infection on amniotic fluid and decidua IL-1-like activity; 5) establish the ontogeny of fetal monocyte IL-1 production; 6) determine the effect of purified human IL-1 and bacterial products in amnion, chorion and decidual production of PGs; and 7) determine whether IL-1 can induce labor in an animal model.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Petz, Larry N; Ziegler, Yvonne S; Schultz, Jennifer R et al. (2004) Fos and Jun inhibit estrogen-induced transcription of the human progesterone receptor gene through an activator protein-1 site. Mol Endocrinol 18:521-32
Petz, Larry N; Ziegler, Yvonne S; Loven, Margaret A et al. (2002) Estrogen receptor alpha and activating protein-1 mediate estrogen responsiveness of the progesterone receptor gene in MCF-7 breast cancer cells. Endocrinology 143:4583-91
Petz, L N; Nardulli, A M (2000) Sp1 binding sites and an estrogen response element half-site are involved in regulation of the human progesterone receptor A promoter. Mol Endocrinol 14:972-85
Romine, L E; Wood, J R; Lamia, L A et al. (1998) The high mobility group protein 1 enhances binding of the estrogen receptor DNA binding domain to the estrogen response element. Mol Endocrinol 12:664-74
Wood, J R; Greene, G L; Nardulli, A M (1998) Estrogen response elements function as allosteric modulators of estrogen receptor conformation. Mol Cell Biol 18:1927-34
Dowling, D D; Romero, R J; Mitchell, M D et al. (1991) Isolation of multiple substances in amniotic fluid that regulate amnion prostaglandin E2 production: the effects of gestational age and labor. Prostaglandins Leukot Essent Fatty Acids 44:253-5
Mitchell, M D; Edwin, S; Romero, R J (1990) Prostaglandin biosynthesis by human decidual cells: effects of inflammatory mediators. Prostaglandins Leukot Essent Fatty Acids 41:35-8