Preterm birth is the leading factor causing neonatal mortality and morbidity.
Inflammation plays a central role in stimulating uterine contractility, which is responsible for approximately one-third of all
preterm births. Recent studies have shown that the
transcription factor Forkhead box O3 (FOXO3) regulates
inflammation in nongestational tissues such as adipocytes and hepatocytes. Thus, in this study, we sought to determine the effect of 1) human term labor on myometrial FOXO3 expression and 2) FOXO3 inhibition and FOXO3 overexpression on proinflammatory and prolabor mediators in human myometrial cells. Higher FOXO3 gene and
protein expression were detected in myometrium obtained from women in labor when compared to samples taken from nonlaboring women. Myometrial cells were isolated from pregnant human myometrium, and FOXO3 silencing was achieved using
siRNA and overexpression using a
cDNA clone. We found that the loss of FOXO3 in myometrial cells was associated with a significant decrease in IL1B-induced
IL6 and
IL8 expression and production,
cyclooxygenase ([COX]-2, official symbol
PTGS2) expression and subsequent
prostaglandin (
PGE2 and
PGF2alpha) release, and
matrix metalloproteinase 9 (MMP9) and
mRNA expression and activity. Conversely, FOXO3 overexpression increased
cytokine expression and secretion,
prostaglandin production, and MMP9 expression in myometrial cells treated with IL1B. In summary, we have identified FOXO3 as an upstream mediator of
inflammation in human myometrium. Thus, FOXO3 may present an alternative therapeutic target for preventing
preterm birth and its associated morbidity and mortality.