HoxA13 Stimulates Myometrial Cells to Secrete IL-1β and Enhance the Expression of Contraction-Associated Proteins

Bipedalism in humans requires regionalization of myometrial function with a contracted lower uterine segment and a relaxed fundus during pregnancy to prevent fetal pressure on the cervix and reversal of this phenotype during labor. The HoxA13 gene is highly expressed in the lower uterine segment before term labor and regulates the regionalization of myometrium contractility. However, how HoxA13 regulates signal pathways to exert its functions remains unclear. Using a gene microarray technique, we profiled HoxA13 transcriptome in myometrial cells containing immune response genes (eg, IL-1β, IL-6, and IL-8) and contraction-associated proteins (CAPs) such as cyclooxygenase-2 (Cox-2) and connexin-43. IL-1β is responsible for mediating HoxA13 actions in up-regulating IL-6, IL-8, Cox-2, and connexin-43 expression. Blocking IL-1β with its inhibitor abolishes these HoxA13 actions. HoxA13-induced IL-1β stimulates the recruitment of activated THP-1 monocytes to myometrial cells, which in turn amplify the secretion of IL-1β, IL-6, and IL-8 through a mutual feed-forward loop between these cell types. As a result, Cox-2 expression is dramatically enhanced. These findings lead us to conclude that HoxA13 increases myometrial cell contractility by enhancing the secretion of IL-1β, resulting in an up-regulation of CAP and other proinflammatory cytokine expression. HoxA13-induced IL-1β in myometrial cells also prompts leukocyte recruitment and further amplifies CAP expression.