title: The Pseudomonas aeruginosa autoinducer 3O-C12 homoserine lactone provokes hyperinflammatory responses from cystic fibrosis airway epithelial cells.
abstract: The discovery of novel antiinflammatory targets to treat inflammation in the cystic fibrosis (CF) lung stands to benefit patient populations suffering with this disease. The Pseudomonas aeruginosa quorum sensing autoinducer N-3-oxododecanoyl homoserine lactone (3O-C12) is an important bacterial virulence factor that has been reported to induce proinflammatory cytokine production from a variety of cell types. The goal of this study was to examine the ability of 3O-C12 to induce proinflammatory cytokine production in normal and CF bronchial epithelial cells, and better understand the cellular mechanisms by which this cytokine induction occurs. 3O-C12 was found to induce higher levels of IL-6 production in the CF cell lines IB3-1 and CuFi, compared to their corresponding control cell lines C38 and NuLi. Systems biology and network analysis revealed a high predominance of over-represented innate immune pathways bridged together by calcium-dependant transcription factors governing the transcriptional responses of A549 airway cells to stimulation with 3O-C12. Using calcium-flux assays, 3O-C12 was found to induce larger and more sustained increases in intracellular calcium in IB3-1 cells compared to C38, and blocking this calcium flux with BAPTA-AM reduced the production of IL-6 by IB3-1 to the levels produced by C38. These data suggest that 3O-C12 induces proinflammatory cytokine production in airway epithelial cells in a calcium-dependent manner, and that dysregulated calcium storage or signalling in CF cells results in an increased production of proinflammatory cytokines.
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Mayer
authors.forename: Jared A
authors.initials: JA
authors.lastname: Sheridan
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Blohmke
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D003550:Cystic Fibrosis / Q000382:microbiology / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D004847:Epithelial Cells / Q000382:microbiology / Q000473:pathology; D006714:Homoserine / Q000031:analogs & derivatives* / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000382:microbiology; D007783:Lactones; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D012137:Respiratory System / Q000382:microbiology / Q000473:pathology*
chemical_list: D016207:Cytokines; D007783:Lactones; C109860:N-(3-oxododecanoyl)homoserine lactone; C085113:Pseudomonas aeruginosa autoinducer; D006714:Homoserine; D015107:4-Butyrolactone; D002118:Calcium