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.
Highlights
Cystic fibrosis (CF) is a chronic pulmonary disease characterized by recurrent and excessive inflammation that causes the destruction of lung tissue, eventually resulting in respiratory failure
Flagellin and IL-1b induced the production of both IL-6 and IL-8 from all four cells with IL-8 production being on the order of 1 to 2-fold higher than IL-6, confirming that 3O-C12 was specific in its ability to induce IL-6
C4 HSL did not induce the production of IL-6 or IL-8 to greater than basal levels in any of the four cell lines tested
Summary
Cystic fibrosis (CF) is a chronic pulmonary disease characterized by recurrent and excessive inflammation that causes the destruction of lung tissue, eventually resulting in respiratory failure. 3O-C12 is a powerful inducer of proinflammatory cytokines such as IL-6 and IL-8 in airway epithelial cells and lung fibroblasts, upregulates inflammatory enzymes such as cyclooxygenase-2 (COX-2) (both in vitro and in vivo) [10,20,21,22], and enhances neutrophil chemotaxis [23]. Taken together, these data suggest that 3O-C12 suppresses the function of key immune networks responsible for bacterial clearance, while simultaneously enhancing inflammatory pathways that promote the pathogenesis of CF
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