15-deoxy-delta(12-14)-prostaglandin-j2 and Premature-Birth

Prematurity is the leading cause of childhood death under the age of five. The aetiology of preterm birth is multifactorial; however, inflammation and infection are the most common causal factors, supporting a potential role for immunomodulation as a therapeutic strategy. 15-Deoxy-Delta-12,14-prostaglandin J2 (15dPGJ2) is an anti-inflammatory prostaglandin and has been shown to delay lipopolysaccharide (LPS) induced preterm labour in mice and improve pup survival. This study explores the immunomodulatory effect of 15dPGJ2 on the transcription factors NF-κB and AP-1, pro-inflammatory cytokines, and contraction associated proteins in human cultured myocytes, vaginal epithelial cell line (VECs) and primary amnion epithelial cells (AECs).. Cells were pre-incubated with 32µM of 15dPGJ2 and stimulated with 1ng/mL of IL-1β as an. 15dPGJ2 inhibited IL-1β-induced activation of NF-κB and AP-1, and expression of IL-6, IL-8, TNF-α, COX-2 and PGE2 in myocytes, with no effect on myometrial contractility or cell viability. Despite inhibiting IL-1β-induced activation of NF-κB, expression of IL-6, TNF-α, and COX-2, 15dPGJ2 led to activation of AP-1, increased production of PGE2 and increased cell death in VECs and AECs.. We conclude that 15dPGJ2 has differential effects on inflammatory modulation depending on cell type and is therefore unlikely to be a useful therapeutic agent for the prevention of preterm birth.

Topics: Amnion; Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Cytokines; Dinoprostone; Epithelial Cells; Female; Humans; Infant, Newborn; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; Mice; Muscle Cells; NF-kappa B; Premature Birth; Prostaglandin D2; RNA, Messenger; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

Nrf2 is a key transcription factor that modulates cell defense mechanisms against endogenous and exogenous stress. Previously, we reported that thrombin increased matrix metalloproteinases and prostaglandin synthesis in human amnion mesenchymal cells.. We sought to determine whether activation of Nrf2 alters the effect of thrombin on prostaglandin synthesis, protease activation, and cytokine release in human amnion. Furthermore, we analyzed the effect of Nrf2 activation on thrombin-induced preterm labor in mice.. Primary human amnion mesenchymal cells and pregnant mice were employed to investigate the effect of Nrf2 on thrombin-induced inflammation and preterm birth.. This was a laboratory-based study using cells and mice.. As expected, thrombin increased cyclooxygenase-2, IL-1β, IL-6, IL-8, and matrix metalloproteinase-1 in amnion mesenchymal cells. Preincubation with Nrf2 activators, diethyl maleate or 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), profoundly repressed thrombin-induced gene expression. In addition, Nrf2 activation inhibited thrombin-induced cyclooxygenase-2 protein levels and secretion of prostaglandin E2, IL-1β, IL-6, IL-8, TNFα, and granulocyte-macrophage colony-stimulating factor in the media. Whereas vehicle and 15d-PGJ2 did not alter gestational length, all pregnant mice treated with thrombin delivered preterm. 15d-PGJ2 delayed thrombin-induced preterm birth significantly.. The results indicate that Nrf2 activation represents a key stress response in amnion mesenchyme cells and in pregnant mice to mitigate the adverse proinflammatory effects of thrombin on the fetal membranes. We suggest, therefore, that pharmacological activation of Nrf2 may prevent the increased risk of preterm premature rupture of the membranes associated with thrombin activation that accompanies subchorionic hemorrhage or bleeding during pregnancy.

Topics: Amnion; Animals; Cyclooxygenase 2; Female; Gestational Age; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Maleates; Matrix Metalloproteinase 1; Mice; NF-E2-Related Factor 2; Pregnancy; Premature Birth; Prostaglandin D2; Thrombin