PT  - JOURNAL ARTICLE
AU  - Chao Zhang
AU  - Lingrui Wang
AU  - Tingting Li
AU  - Wei Mao
AU  - Bo Liu
AU  - Jinshan Cao
TI  - EP2/4 receptors promotes the synthesis of PGE2 increasing tissue damage in bovine endometrial explants induced by Escherichia coli
AID  - 10.1124/jpet.119.262444
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.119.262444
4099  - http://jpet.aspetjournals.org/content/early/2019/11/18/jpet.119.262444.short
4100  - http://jpet.aspetjournals.org/content/early/2019/11/18/jpet.119.262444.full
AB  - The bovine uterine is easily contaminated with bacteria during coitus or parturition. A previous study suggested that Prostaglandin E2 (PGE2) promoted Escherichia coli (E. coli)-infected bovine endometrial tissues inflammatory damage via cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1. However, the pro-inflammatory effect of PGE2 was regulated by which PGE2 receptors remains unclear. In this study, we evaluated the effect of PGE2 and its mediated receptors on E. coli-infected endometrium explants isolated from the bovine uterus. The E. coli–infected bovine endometrial explants were cultured in vitro, and the study used EP2/4 receptors agonists to investigate the responses of COX-2, mPGES-1, PGE2, pro-inflammatory factors and damage-associated molecular patterns (DAMPs). The expression of COX-2, mPGES-1, PGE2, pro-inflammatory factors, and DAMPs was significantly increased after infection with E. coli; however, the high expression levels caused by E. coli were reduced following treatment with COX-2 and mPGES-1 inhibitors. In addition, the expression levels of COX-2, mPGES-1, PGE2, pro-inflammatory factors, and DAMPs were higher in treatment with EP2/4 receptors agonists in E. coli-infected endometrium explants, and their promotable effects were effectively blocked by EP2/4 receptors antagonists. These findings provide evidence that PGE2 may promote the progress of inflammation in endometrial explants infected with E. coli in bovines. Furthermore, EP2/4 may be involved in a positive feedback loop for COX-2 and mPGES-1 expression, and this may be responsible for the pro-inflammatory reaction of PGE2 in E. coli-infected uteri of bovines.SIGNIFICANCE STATEMENT In this study, we investigated EP2/4 of PGE2 receptors that were possibly involved in E. coli-infected explants of the endometrium of dairy bovines. The results further suggested that accumulation of PGE2 might play an essential role in tissue damage of endometrial explants infected with E. coli via promoting pro-inflammatory factors IL-1β, IL-6, IL-8, TNF-α, HMGB-1 and HABP1 production. EP2/4 receptors are involved in a positive feedback loop for COX-2 and mPGES-1 expression, thus enhancing PGE2 production. Furthermore, these two receptors mediate the pro-inflammatory action of PGE2 by increasing pro-inflammatory factors and DAMPs secretion and aggravating damage of explants.