PGE2 increases inflammatory damage in Escherichia coli-infected bovine endometrial tissue in vitro via the EP4-PKA signaling pathway.

Abstract

Endometritis is the most common bovine uterine disease following parturition. The role of prostaglandin E2 (PGE2) in the regulation of endometrial inflammation and repair is well understood. Excess PGE2 is also generated in multiple inflammatory diseases, including endometritis. However, it remains unclear whether PGE2 is associated with pathogen-induced inflammatory damage to the endometrium. To clarify the role of PGE2 in pathogen-induced inflammatory damage, this study evaluated the production of PGE2, inflammatory factors, and damage-associated molecular patterns (DAMPs) in cultured Escherichia coli-infected bovine endometrial tissue. PGE2 production was significantly higher in E. coli-infected tissue, and in E. coli-infected tissue treated with 15-prostaglandin dehydrogenase (15-PGDH) inhibitors, as compared to uninfected tissue. Phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and microsomal prostaglandin E synthase-1 (mPGES-1) were also upregulated in E. coli-infected tissue, while concentrations of arachidonic acid (AA), leukotrienes, DAMPs, and other proinflammatory factors increased. The accumulation of PGE2 clearly damaged the cultured tissue. Treatment with the COX-2, mPGES-1, EP4, and protein kinase A (PKA) inhibitors decreased the production of PGE2, inflammatory factors, and DAMPs, simultaneously alleviating the E. coli-induced endometrial tissue damage. Therefore, the PGE2 that was generated by COX-2 and mPGES-1 accumulated, and this pathogenic PGE2 increased inflammatory damage by upregulating inflammatory factors and DAMPs in E. coli-infected bovine endometrial tissue. This upregulation of inflammatory factors and DAMPs might be regulated by the EP4-PKA signaling pathway.