Prostaglandin E2 promotes nitric oxide synthase 2, platelet-activating factor receptor, and matrix metalloproteinase-2 expression in Escherichia coli-challenged ex vivo endometrial explants via the prostaglandin E2 receptor 4/protein kinase a signaling pathway

Abstract

Prostaglandin E₂ (PGE₂) is an inflammatory mediator involved in the pathogenesis of several chronic inflammatory conditions, including endometritis. Previous studies have shown that PGE₂ accumulates in Escherichia coli-challenged ex vivo endometrial explants, increasing the expression of pro-inflammatory factors and aggravating tissue damage; these alterations are linked to key enzymes involved in the synthesis of PGE₂, including cyclooxygenases-2 (COX-2) and microsomal PGES-1 (mPGES-1). In this study, we aimed to investigate whether administration of PGE₂ modulated the activities of nitric oxide synthase 2 (NOS2), platelet-activating factor receptor (PAFR), and matrix metalloproteinase (MMP)-2 in E. coli-challenged ex vivo bovine endometrial explants. Our findings showed that COX-2 and mPGES-1 inhibitors significantly reduced NOS2, PAFR, and MMP-2 expression in the E. coli-challenged ex vivo endometrial explants. In addition, NOS2, PAFR, and MMP-2 expression levels were strongly increased in response to treatment with 15-prostaglandin dehydrogenase inhibitors in the E. coli-challenged ex vivo endometrial explants. However, these stimulatory effects could be blocked by PGE₂ receptor 4 (EP4) and protein kinase A (PKA) inhibitors. Overall, these findings show that pathogenic PGE₂ upregulated NOS2, PAFR, and MMP-2 expression, which may enhance inflammatory damage via the EP4/PKA signaling pathway in E. coli-challenged ex vivo endometrial explants.

Keywords: Endometrium; Escherichia coli; Inflammation; Prostaglandin E(2).