Chorioamnionitis frequently precedes both genital tract and placental inflammation and is both a primary cause of maternal morbidity and a major antecedent of preterm premature rupture of the membranes (PPROM) as well as preterm delivery (PTD). In most cases of chorioamnionitis , neutrophils dominate the decidua. In a subset of these cases , a predominance of monocytes is uniquely associated with both neonatal intraventricular hemorrhage and death. The multifunctional cytokine , interleukin-6 , promotes local monocyte dominance via several mechanisms. In this study , immunostaining of placental sections revealed significantly higher interleukin-6 HSCOREs in decidual cells (DCs) but not in interstitial trophoblasts , in chorioamnionitis versus gestational agematched control placentas (P < 0.05). In confluent leukocyte-free term DCs , secreted interleukin-6 levels in incubations with estradiol-17 were increased 2500-fold by IL-1 (P < 0.05). This up-regulation was inhibited by more than 50% in parallel incubations that included medroxyprogesterone acetate (n ؍ 12, P < 0.05). Western blotting data confirmed these enzyme-linked immunosorbent assay results; quantitative RT-PCR findings demonstrated corresponding changes in interleukin-6 mRNA levels. Specific inhibitors of signaling for both nuclear factor-B activation and p38-mitogen-activated protein kinase , but not for protein kinase C , significantly decreased IL-1-enhanced interleukin-6 expression levels in cultured DCs. In conclusion , in situ and in vitro results indicate that significantly enhanced interleukin-6 expression levels in DCs during chorioamnionitis could be pivotal in skewing decidual monocyte differentiation to macrophages.