15-Deoxy-Delta-12,14-prostaglandin J2 modulates pro-labour and pro-inflammatory responses in human myocytes, vaginal and amnion epithelial cells

• Published in: Frontiers in endocrinology (Lausanne) Vol. 13; p. 983924
• Main Authors: Rasheed, Zahirrah Bm, Lee, Yun S, Kim, Sung H, Teoh, Tg, MacIntyre, David A, Bennett, Phillip R, Sykes, Lynne
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 21.09.2022
• Subjects: activator protein (AP)-1; Amnion; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 - pharmacology; cytokines; Cytokines - metabolism; Dinoprostone - metabolism; Dinoprostone - pharmacology; Dinoprostone - therapeutic use; Endocrinology; Epithelial Cells - metabolism; Female; Humans; Infant, Newborn; inflammation; Inflammation - metabolism; Interleukin-6; Interleukin-8 - metabolism; Interleukin-8 - pharmacology; Interleukin-8 - therapeutic use; Lipopolysaccharides; Mice; Muscle Cells - metabolism; NF-kappa B - metabolism; nuclear factor - kappa B (NF - κB); Premature Birth; preterm labour (PTL); Prostaglandin D2 - analogs & derivatives; prostaglandins; RNA, Messenger - metabolism; Transcription Factor AP-1 - metabolism; Transcription Factor AP-1 - pharmacology; Transcription Factor AP-1 - therapeutic use; Tumor Necrosis Factor-alpha - metabolism; nuclear factor - kappa B (NF - κB); activator protein (AP)-1; inflammation; preterm labour (PTL); 15dPGJ2; prostaglandins; cytokines
• ISSN: 1664-2392; 1664-2392
• DOI: 10.3389/fendo.2022.983924

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 model of inflammation. Western immunoblotting was used to detect phosphorylated p-65 and phosphorylated c-Jun as markers of NF-κB and AP-1 activation, respectively. mRNA expression of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α was examined, and protein expression of COX-2 and PGE2 were detected by western immunoblotting and ELISA respectively. Myometrial contractility was examined using a myograph. 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.