CFTR is a negative regulator of NFκB mediated innate immune response

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© 2009 Vij et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: Dysfunctional CFTR in the airways is associated with elevated levels of NFkB mediated IL-8 signaling leading to neutrophil chemotaxis and chronic lung inflammation in cystic fibrosis. The mechanism(s) by which CFTR mediates inflammatory signaling is under debate. Methodology/Principal Findings: We tested the hypothesis that wt-CFTR down-regulates NFkB mediated IL-8 secretion. We transiently co-expressed wt-CFTR and IL-8 or NFkB promoters driving luciferase expression in HEK293 cells. Wt-CFTR expression in HEK293 cells suppresses both basal and IL1b induced IL-8, and NFkB promoter activities as compared to the control cells transfected with empty vector (p<0.05). We also confirmed these results using CFBE41o- cells and observed that cells stably transduced with wt-CFTR secrete significantly lower amounts of IL-8 chemokine as compared to nontransfected control cells. To test the hypothesis that CFTR must be localized to cell surface lipid rafts in polarized airway epithelial cells in order to mediate the inflammatory response, we treated CFBE41o- cells that had been stably transduced with wt-CFTR with methyl-β-cyclodextrin (CD). At baseline, CD significantly (p<0.05) induced IL-8 and NFκB reporter activities as compared to control cells suggesting a negative regulation of NFκB mediated IL-8 signaling by CFTR in cholesterol-rich lipid rafts. Untreated cells exposed to the CFTR channel blocker CFTR-172 inhibitor developed a similar increase in IL-8 and NFκB reporter activities suggesting that not only must CFTR be present on the cell surface but it must be functional. We verified these results in vivo by comparing survival, body weight and pro-inflammatory cytokine response to P. aeruginosa LPS in CFTR knock out (CFKO) mice as compared to wild type controls. There was a significant (p<0.05) decrease in survival and body weight, an elevation in IL-1β in whole lung extract (p<0.01), as well as a significant increase in phosphorylated IκB, an inducer of NFκB mediated signaling in the CFKO mice. Conclusions/Significance: Our data suggest that CFTR is a negative regulator of NFκB mediated innate immune response and its localization to lipid rafts is involved in control of inflammation.




Vij, N., Mazur, S., & Zeitlin, P. L. (2009). CFTR is a negative regulator of NFκB mediated innate immune response. PLoS ONE, 4(2).

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