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Abstract
15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an anti-inflammatory downstream product of the cyclooxygenase enzymes. It has been implicated to play a protective role in a variety of inflammatory mediated diseases, including rheumatoid arthritis, neural damage, and myocardial infarctions. Here we show that 15d-PGJ2 also plays a role in Salmonella infection. Salmonella enterica Typhimurium is a Gram-negative facultative intracellular pathogen that is able to survive and replicate inside phagocytic immune cells, allowing for bacterial dissemination to systemic sites. Salmonella species cause a wide range of morbidity and mortality due to gastroenteritis and typhoid fever. Previously we have shown that in mouse models of typhoid fever, Salmonella infection causes a major perturbation in the prostaglandin pathway. Specifically, we saw that 15d-PGJ2 production was significantly increased in both liver and feces. In this work we show that 15d-PGJ2 production is also significantly increased in macrophages infected with Salmonella. Furthermore, we show that the addition of 15d-PGJ2 to Salmonella infected RAW264.7, J774, and bone marrow derived macrophages is sufficient to significantly reduce bacterial colonization. We also show evidence that 15d-PGJ2 is reducing bacterial uptake by macrophages. 15d-PGJ2 reduces the inflammatory response of these infected macrophages, as evidenced by a reduction in the production of cytokines and reactive nitrogen species. The inflammatory response of the macrophage is important for full Salmonella virulence, as it can give the bacteria cues for virulence. The reduction in bacterial colonization is independent of the expression of Salmonella virulence genes SPI1 and SPI2, and is independent of the 15d-PGJ2 ligand PPAR-γ. 15d-PGJ2 also causes an increase in ERK1/2 phosphorylation in infected macrophages. In conclusion, we show here that 15d-PGJ2 mediates the outcome of bacterial infection, a previously unidentified role for this prostaglandin.
Highlights
Prostaglandins (PG) are a class of lipid hormones responsible for a wide range of functions within the body
Because Salmonella actively replicates in macrophages, we examined RAW264.7 macrophage cells infected with Salmonella to determine if 15d-PGJ2 production was induced in these cells, as observed in mice
The potential role of 15d-PGJ2 during bacterial infection was initially considered because of the results of a metabolomics screen recently performed by our lab [40]
Summary
Prostaglandins (PG) are a class of lipid hormones responsible for a wide range of functions within the body. PGs are synthesized from arachidonic acid that is released from the cell membrane by phospholipase A2 and modified by the cyclooxygenase enzymes (COX1 and COX2) to enter the PG pathway (Figure 1) [1,2]. COX2-derived PGs are involved in a variety of pro- and anti-inflammatory processes [2,3]. The involvement of COX1 and COX2 in regulating inflammation is evidenced by the increased cardiovascular risk associated with the inhibition of COX2 [4], and the increased susceptibility to colitis in mice lacking these two enzymes [5]. Two waves of COX2 activity have been identified: the first (early) activity is associated with the pro-inflammatory response, whereas the second wave mediates the resolution of inflammation [6], and is associated with high levels of PGD2 and 15-deoxy-D12,14-PGJ2 (hereafter referred to as 15d-PGJ2) [1,6]
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