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

• Published in: Journal of lipid research Vol. 63; no. 11; p. 100294
• Main Authors: Zhang, Fan, Sun, Kang, Wang, Wang-Sheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2022; American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: 15(S)-hydroxyeicosatetraenoic acid; Amnion - metabolism; Animals; arachidonic acid; Cyclooxygenase 2 - metabolism; cyclooxygenase-2; Dinoprostone; eicosanoids; Female; Humans; Hydroxyeicosatetraenoic Acids - pharmacology; inflammation; interleukin-1β; lipopolysaccharide; lipoxygenase 15; metabolomics; Mice; Parturition - metabolism; Pregnancy; Premature Birth - metabolism; serum amyloid A1; lipoxygenase 15; cyclooxygenase-2; ALOX; LPS; interleukin-1β; PNL; eicosanoids; serum amyloid A1; TNL; inflammation; metabolomics; dpc; arachidonic acid; AA; PGE2; mPGES-1; qRT-PCR; IL-1β; COX; PPARγ; PG; SAA1; TL; lipopolysaccharide; PL; 15(S)-hydroxyeicosatetraenoic acid
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1016/j.jlr.2022.100294

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. Prostaglandin E2 (PGE2) synthesized from the cyclooxygenase (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 parturition remains elusive. Here, we screened such eicosanoids 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 ineffective on its own, it potently potentiated the activation of NF-κB by inflammatory mediators including lipopolysaccharide, interleukin-1β, and serum amyloid A1, resulting in the amplification of COX-2 expression and PGE2 production in amnion fibroblasts. 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 parturition. 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 parturition. Interruption of this feed-forward loop may be of therapeutic value for the treatment of preterm birth.
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