Identification of a Feed-Forward Loop Between 15(S)-HETE and PGE2 in Human Amnion at Parturition

Human parturition is associated with massive arachidonic acid (AA) mobilization in the amnion, indicating that large amounts of AA-derived eicosanoids are required for parturition. Prosta-glandin E2 (PGE2) synthesized from the cyclo-oxygenase (COX) pathway is the best characterized AA-derived eicosanoid in the amnion which plays a pivotal role in parturition. The existence of any other pivotal AA-derived eicosanoids involved in parturi-tion remains elusive. Here, we screened such eicosa-noids in human amnion tissue with AA-targeted metabolomics and studied their role and synthesis in parturition by using human amnion fibroblasts and a mouse model. We found that lipoxygenase (ALOX) pathway-derived 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) and its synthetic enzymes ALOX15 and ALOX15B were significantly increased in human amnion at parturition. Although 15(S)-HETE is inef-fective on its own, it potently potentiated the activa-tion of NF-kappa B by inflammatory mediators including lipopolysaccharide, interleukin-1 beta, and serum amy-loid A1, resulting in the amplification of COX-2 expression and PGE2 production in amnion fibro-blasts. In turn, we determined that PGE2 induced ALOX15/15B expression and 15(S)-HETE production through its EP2 receptor-coupled PKA pathway, thereby forming a feed-forward loop between 15(S)-HETE and PGE2 production in the amnion at partu-rition. Our studies in pregnant mice showed that 15(S)-HETE injection induced preterm birth with increased COX-2 and PGE2 abundance in the fetal membranes and placenta. Conclusively, 15(S)-HETE is identified as another crucial parturition-pertinent AA-derived eicosanoid in the amnion, which may form a feed-forward loop with PGE2 in parturi-tion. Interruption of this feed-forward loop may be of therapeutic value for the treatment of preterm birth.

Automated summary

Human parturition involves the mobilization of arachidonic acid (AA) and the synthesis of AA-derived eicosanoids, particularly prostaglandin E2 (PGE2), which plays a key role. This study identified another important AA-derived eicosanoid, 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), in the amnion and discovered a feed-forward loop between 15(S)-HETE and PGE2 in parturition. Targeting this loop may have therapeutic potential for the treatment of preterm birth.