15-Deoxy-Δ12,14-prostaglandin J2 inhibits macrophage colonization by Salmonella enterica serovar Typhimurium.
15-deoxy-Δ(12,14)-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.
Michael Smith Laboratories, The University of British Columbia, Vancouver, British Columbia, Canada.
Michelle M C
MM
Buckner
L Caetano M
LC
Antunes
Navkiran
N
Gill
Shannon L
SL
Russell
Stephanie R
SR
Shames
B Brett
BB
Finlay
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015169:Colony Count, Microbial; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial / Q000235:genetics; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007109:Immunity / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D026361:Reactive Nitrogen Species / Q000378:metabolism; D012480:Salmonella Infections / Q000382:microbiology / Q000473:pathology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity; D014774:Virulence / Q000187:drug effects / Q000235:genetics
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D016207:Cytokines; D047495:PPAR gamma; D026361:Reactive Nitrogen Species; D016718:Arachidonic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D015230:Prostaglandin D2