Preterm birth is a major cause of perinatal mortality. The nature and origin of the signals governing the onset of labor in the human remain obscure. Among the African Americans the preterm birth rate is twice as high as the rest of the population. Because medical, psychological and behavioral risk factors do not explain this increased risk of preterm labor, it is crucial to identify predictive markers and mechanisms which may provide insight(s) into the pathophysiology of premature birth. A regulatory link between physiological and immunological mechanisms is well documented in normal gestations. Abnormal pregnancies and premature deliveries are also thought to be associated with altered immune responses and cytokine profiles. Proinflammatory cytokines such as TNF-a are important in the initiation of parturition. In this context, we hypothesize that IL-10, a potent anti-inflammatory cytokine, is down-regulated in the placental-decidual microenvironment as part of the """"""""normal mechanism"""""""" for the onset of labor. Dysregulation of IL-10 may predispose to parturition by inducing pro-inflammatory cytokines, collagen degrading matrix metalloprotein, and prostaglandins. Our preliminary data suggest that IL-10 expression is reduced in placental tissue sections and isolated cytotrophoblast from preterm deliveries. Although the link between preterm birth and cytokines is multifactorial, we hypothesize that single base pair polymorphism in the lL-10 gene promoter lead to reduced production in the placental microenvironment and predispose to preterm labor. We will use a cohort of African American (AA), European American (EA), European (E), and Japanese American (JA) populations to define allele frequency of IL-10 promoter polymorphism in these distinct populations with different risks of preterm birth. International and National investigators and clinical centers will be enrolled to achieve the Specific Aims:
Aim 1 tests the hypothesis that decidual and placental tissues from a significant subgroup of preterm labor deliveries exhibit diminished lL-10 expression detected by immunological and molecular techniques;
Aim 2 documents the association of polymorphism in the IL-10 gene promoter with preterm birth analyzed by PCR, restriction fragment length polymorphism (RFLP), and sequencing;
Aim 3 tests the hypothesis that polymorphic alterations in the lL-10 gene promoter result in decreased transcriptional activity leading to reduced protein production;
and Aim 4 focuses on the hypothesis that endogenous hsp60 expressed in the decidua or the placenta induces expression of anti-inflammatory cytokines such as lL-10 whereas bacteriologic hsp60 modeled by chlamydia represses lL-10 and upregulates inflammatory cytokines. These studies will identify important immunogenetic markers for preterm births, articularly in the African American population.
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