Grant: Operating Grant

The most important health problem of pregnancy and birth is premature delivery. Unfortunately, there are no effective means to treat women who will delivery early to delay birth, prolong pregnancy, and improve newborn outcomes. Recent evidence from our established, experienced collaborative team has suggested that two inflammatory mediators, interleukins (IL)-1 beta (IL-1b) and IL-6, affect the timing of birth in animal models of pregnancy. We have developed many new tools to study the roles of these interleukins on the timing of birth. We believe these two mediators stimulate the recruitment of circulating white blood cells (or leukocytes) to the uterus, where they cause more leukocytes to be attracted, and release more inflammatory mediators, to convert the uterus of pregnancy into the uterus of delivery. When IL-1b is administered, animals deliver early; when the gene for IL-6 is absent, delivery is postponed. Two members of our team have developed new pharmacological antagonists to IL-1b and IL-6, and a third member has developed new mouse models where the IL-6 gene is absent. We have also found that depleting circulating white blood cells (or leukocytes), especially macrophages, a rich source of IL-1b and IL-6, leads to delayed delivery. Uterine cells respond to IL-1b and IL-6 by releasing inflammatory mediators, and our team has developed a new test to assess leukocyte activation as preparation for infiltration into the uterus. We will use all these tools to test whether IL-1b and IL-6 are necessary for the process of birth and whether our new antagonists are effective in blocking premature delivery. If they are, these antagonists can be commercialized by our investigators to develop new treatments for prolonging pregnancy in women at risk for premature delivery.