Prostaglandin E2 (PGE2) is an important immunomodulatory molecule that is part of a larger group of bioactive lipids known as eicosanoids. PGE2 has long been reported to have conflicting roles in the regulation of inflammation. For example, some effects are primarily anti‐inflammatory and other roles that mediate inflammation. During intracellular infection with Gram‐negative bacteria, host macrophages form complexes called inflammasomes. Inflammasomes drive activation and secretion of inflammatory cytokines such as IL‐1β that signal nearby cells in the process of inflammatory cell death called pyroptosis. PGE2 is reported to inhibit NLRP3 inflammasome activation and enhance NLRC4 inflammasome activation. Since both NLRP3 and NLRC4 inflammasomes mediate IL‐1β secretion, the PGE2's function in the inflammatory processes does not seem to be clear. Previous studies relied on LPS stimulation of macrophages in place of bacterial infection. In this study, we used an infection model of THP‐1 human macrophages with Salmonella enterica Typhimurium (St) and Yersinia enterocolitica (Ye) that suggests PGE2 plays a vital role in enhancing the transcription and secretion of IL‐1β upon inflammasome activation. Interestingly, distinct virulence strategies between St and Ye are reflected in the alteration of COX‐2 and resulting PGE2 biosynthesis by these pathogens. Ye virulence factors inhibit COX‐2 expression and thus decrease the amount of PGE2 secreted during infection. St, in contrast, activates COX‐2 and enhances PGE2 production. In our studies, PGE2 enhances bacterial load of St inside macrophages 48 hours post infection, but it decreases intracellular Ye. Finally, our results suggest that PGE2 primarily enhances the transcription of pro‐inflammatory cytokines while repressing anti‐inflammatory processes such as resource scavenging and matrix remodeling.Support or Funding InformationThis study was supported by a fund no. 2016‐31200‐06012 from the National Institute of Food and Agriculture (NIFA), https://doi.org/10.13039/100005825, National Institutes of Health (NIH) fund no. 5P20GM103646‐02, https://doi.org/10.13039/100000002, as well as MS Center for Food Safety and Post‐harvest Technology Grant Program (USDA‐ARS SCA 58‐6066‐7081) and NIH1R15ES015348‐02. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.