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Prostaglandin E₂ receptors differentially regulate the output of proinflammatory cytokines in myometrial cells from term pregnant women

ZHANG You-Yi¹, LIU Wei-Na^1,2, YOU Xing-Ji¹, GU Hang³, XU Chen^1,4, NI Xin^1,5,*

¹Department of Physiology, Navy Military Medical University (Second Military Medical University), Shanghai 200433, China；²Department of Gynecology, Chinese PLA 413th Hospital, Zhoushan 316000, China；³Department of Obstetrics and Gynecology, Changhai Hospital, Shanghai 200433, China；⁴Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China；⁵Research Center of Molecular Metabolomics, Xiangya Hospital, Central Southern University, Changsha 410008, China

Abstract

Prostaglandin (PG) E2 plays critical roles during pregnancy and parturition. Emerging evidence indicates that human labour is an inflammatory event. We sought to investigate the effect of PGE2 on the output of proinflammatory cytokines in cultured human uterine smooth muscle cells (HUSMCs) from term pregnant women and elucidate the role of subtypes of PGE2 receptors (EP1, EP2, EP3 and EP4). After drug treatment and/or transfection of each receptor siRNA, the concentrations of inflammatory secreting factors in HUSMCs culture medium were detected by the corresponding ELISA kits. The results showed that, PGE2 increased interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) output, decreased chemokine (c-x-c motif) ligand 8 (CXCL8) output in a dose-dependent manner, but had no effect on IL-1β and chemokine (c-c motif) ligand 2 (CCL-2) secretion of HUSMCs. EP1/EP3 agonist 17-phenyl-trinor-PGE2 stimulated IL-6 and TNFα whilst suppressing IL-1β and CXCL8 output. The effects of 17-phenyl-trinor-PGE2 on IL-1β and CXCL8 secretion were remained whereas its effect on IL-6 and TNFα output did not occur in the cells with EP3 knockdown. The stimulatory effects of 17-phenyl-trinor-PGE2 on IL-6 and TNFα were remained whereas the inhibitory effects of 17-phenyl-trinor-PGE2 on IL-1β secretion was blocked in the cells with EP1 knockdown. Either of EP2 and EP4 agonists stimulated IL-1β and TNFα output, which was reversed by EP2 and EP4 siRNA, respectively. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked EP1/EP3 modulation of TNFα and CXCL8 output. PI3K inhibitor LY294002 and P38 inhibitor SB202190 blocked 17-phenyl-trinor-PGE2-induced IL-1β and IL-6 output, respectively. The inhibitors of adenylyl cyclase and PKA prevented EP2 and EP4 stimulation of IL-1β and TNFα output, whereas PLC and PKC inhibitors blocked EP2- and EP4-induced TNFα output but not IL-1β output. Our data suggest that PGE2 receptors exhibit different effects on the output of various cytokines in myometrium, which can subtly modulate the inflammatory microenvironment in myometrium during pregnancy.  

Key words: myometrium; prostaglandin E2; proinflammatory cytokines; pregnancy

Received: 2018-11-22　　Accepted: 2019-01-22

Corresponding author: 倪鑫　　E-mail: nixin@smmu.edu.cn

DOI: 10.13294/j.aps.2019.0028

Citing This Article：

ZHANG You-Yi, LIU Wei-Na, YOU Xing-Ji, GU Hang, XU Chen, NI Xin. Prostaglandin E₂ receptors differentially regulate the output of proinflammatory cytokines in myometrial cells from term pregnant women. Acta Physiol Sin 2019; 71 (2): 248-260