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• PGE 2 promotes cytokines and DAMPs expression in heat killed S. aureus treated bovine endometrial tissue regulated by EP4-p38 MAPK pathway. • S. aureus adhere and invade into bovine endometrial epithelial cells associated with PGE 2 generation. • The strategy of decreasing PGE 2 accumulation is helpful in reducing the inflammation stage caused by S. aureus. S. aureus isolated from bacterial bovine endometritis is common in epidemiological reports, but is often ignored as a subclinical pathogenic microorganism. In a previous study, we showed that live S. aureus (LSA) and heat killed S. aureus (HK–SA) induce different inflammatory responses in bovine endometrial tissue, and possibly being associated with the accumulation of prostaglandin E2 (PGE 2). Thus, in this study, we varied PGE 2 concentrations using inhibitors or agonists in HK–SA-treated bovine endometrial tissues. The results demonstrated that PGE 2 has a positive relationship with IL-6, TNF-α, and damage-associated molecular patterns (DAMPs; e.g., HMGB-1 and HABP-1) expression and tissues damage, and is regulated by the EP4-p38 MAPK pathway. We concluded that lipoproteins of S. aureus are associated with PGE 2 generation. To further explore the relationship between LSA and PGE 2 accumulation, we used the S. aureus strain SA113 lipoprotein knockout (SA113Δlpl) to infect bovine endometrial epithelial cells (BECs). LSA decreased PGE 2 , cAMP, EP4, IL-6, IL-8, cAMP secretion, and the MAPK and PKA signaling pathways when infected with SA113Δlpl, as compared with SA113-infected groups. Moreover, the adhesion and invasion of BECs were similarly downregulated when lipoproteins in S. aureus were knocked out. The results of this study show that PGE 2 is involved in both HK–SA- and LSA-induced inflammatory responses in the bovine endometrium. We suggest that S. aureus infection is associated with bovine endometritis, and although HK–SA and LSA induce different inflammatory responses, the strategy of decreasing PGE 2 accumulation is helpful in reducing the inflammation stage caused by S. aureus. [ABSTRACT FROM AUTHOR]