CYTOKINE REGULATION OF UTERINE OXYTOCIN RECEPTOR

Delivery before 37 weeks of pregnancy occurs in 7% of all pregnancies and accounts for as much as 90% of all neonatal morbidity and mortality. Despite improved tocolytic therapy and increased pregnancy surveillance, efforts to reduce the preterm birth rate in the last 20 years have largely been unsuccessful. A lack of knowledge of the events responsible for the onset of normal term labor accounts for our inability to prevent preterm delivery. Oxytocin, however, clearly plays a role in the maintenance if not initiation of both term and preterm labor. Oxytocin receptors in both the myometrium and decidua increase sharply immediately prior to labor. The events responsible for increased oxytocin receptor expression in human pregnancy are unknown. The cause for 70% of all cases of preterm labor is unknown, however, 20% of all cases are the result of intraamniotic infection. Intraamniotic infection results in the production of inflammatory cytokines, including interleukin-1 (IL-1). Interleukin-1 initiates preterm labor through the production of decidual uterotonic prostaglandins. Early infection- induced preterm labor is arrested by the decidual production of anti- inflammatory cytokines, interleukin-1 receptor antagonist (IL-1ra) and transforming growth factor beta (TGF beta) which block the action of IL-1. The role of IL-1 in the regulation of oxytocin receptor has not been investigated. Preliminary data show that IL-1 treatment of human myometrial cells in culture results in a time- and dose-dependent down- regulation of oxytocin receptor binding and a reduction in oxytocin receptor function. The downregulation of prematurely induced uterine oxytocin receptors by IL-1 may be another "protective" mechanism limiting the preterm labor process in early infection. The objective of this grant proposal is to study the cytokine regulation of the myometrial and decidual oxytocin receptor. Specific aims will focus on the effect of IL-1 on oxytocin receptor function, including IP3, prostaglandin, and contraction production. Mechanisms responsible for loss of oxytocin receptor binding, including gene transcription, receptor internalization, and degradation will be investigated. The antagonism of IL-1 by IL-lra and TGF beta will be studied. A detailed understanding of the regulation of uterine oxytocin receptors will increase the overall understanding of mechanisms of labor.