title: The bacterial quorum-sensing signal molecule N-3-oxo-dodecanoyl-L-homoserine lactone reciprocally modulates pro- and anti-inflammatory cytokines in activated macrophages.
abstract: The bacterial molecule N-3-oxo-dodecanoyl-l-homoserine lactone (C12) has critical roles in both interbacterial communication and interkingdom signaling. The ability of C12 to downregulate production of the key proinflammatory cytokine TNF-α in stimulated macrophages was suggested to contribute to the establishment of chronic infections by opportunistic Gram-negative bacteria, such as Pseudomonas aeruginosa. We show that, in contrast to TNF-α suppression, C12 amplifies production of the major anti-inflammatory cytokine IL-10 in LPS-stimulated murine RAW264.7 macrophages, as well as peritoneal macrophages. Furthermore, C12 increased IL-10 mRNA levels and IL-10 promoter reporter activity in LPS-stimulated RAW264.7 macrophages, indicating that C12 modulates IL-10 expression at the transcriptional level. Finally, C12 substantially potentiated LPS-stimulated NF-κB DNA-binding levels and prolonged p38 MAPK phosphorylation in RAW264.7 macrophages, suggesting that increased transcriptional activity of NF-κB and/or p38-activated transcription factors serves to upregulate IL-10 production in macrophages exposed to both LPS and C12. These findings reveal another part of the complex array of host transitions through which opportunistic bacteria downregulate immune responses to flourish and establish a chronic infection.
authors.affiliation: Department of Biochemistry and Molecular Biology, Life Sciences Institute, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Glucksam-Galnoy
authors.forename: Roy
authors.initials: R
authors.lastname: Sananes
authors.forename: Nava
authors.initials: N
authors.lastname: Silberstein
authors.forename: Pnina
authors.initials: P
authors.lastname: Krief
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kravchenko
authors.forename: Michael M
authors.initials: MM
authors.lastname: Meijler
authors.forename: Tsaffrir
authors.initials: T
authors.lastname: Zor
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000502:physiology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008164:Luminescent Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000472:pathogenicity; D053038:Quorum Sensing / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008164:Luminescent Proteins; D014409:Tumor Necrosis Factor-alpha; C088386:homoserine lactone; D015107:4-Butyrolactone