Prostaglandin E2 Represses Interleukin 1 Beta-Induced Inflammatory Mediator Output

Inflammatory mediators, including prostaglandins, cytokines, and chemokines, are strongly implicated in the mechanism of human labor, though their precise roles remain unknown. Here we demonstrate that interleukin 1 beta (IL-1beta) significantly increased the expression and release of interleukin-8 (CXCL8), monocyte chemotactic protein-1 (CCL2), and granulocyte mac-rophage colony-stimulating factor (CSF2) by primary human myometrial cells. However, this effect was repressed by prostaglandin E2 (PGE2). As PGE2 can activate four distinct PGE2 receptors (EP1, EP2, EP3, and EP4) to elicit various responses, we sought to define the EP receptor(s) responsible for this repression. Using selective EP receptor agonists and a selective EP4 antagonist, we show that PGE2 mediates the repression of IL-1beta-induced release of CXCL8, CCL2, and CSF2 via activation of the EP2 and EP4 receptors. The use of siRNA gene-specific knockdown further confirmed a role for both receptors. Real-time RT-PCR demonstrated that EP2 was the most highly expressed of all four EP receptors at the mRNA level in human myometrial cells, and immunocytochemistry showed that EP2 protein is abundantly present throughout the cells. Interestingly, PGE2 does not appear to reduce mRNA expression of CXCL8, CCL2, and CSF2. Our results demonstrate that PGE2 can elicit anti-inflammatory responses via activation of the EP2 and EP4 receptors in lower segment term pregnant human myometrial cells. Further elucidation of the EP receptor-mediated signaling pathways in the pregnant human uterus may be beneficial for optimizing the maintenance of pregnancy, induction of labor or indeed treatment of preterm labor