Pseudomonas aeruginosa Quorum-Sensing Molecule Homoserine Lactone Modulates Inflammatory Signaling through PERK and eI-F2 

  • Grabiner M
  • Fu Z
  • Wu T
 et al. 
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Abstract

Pseudomonas aeruginosa (PA) secrete N-(3-oxododecanoyl)-homoserine lactone (HSL-C12) as a quorum-sensing molecule to regulate bacterial gene expression. Since HSL-C12 is membrane- permeant, multiple cell types in PA-infected airways may be exposed to HSL-C12, especially adjacent to biofilms where local [HSL-C12] may be high. Previous reports showed that HSL-C12 causes both pro- and anti-inflammatory effects. To characterize HSL-C12’s pro- and anti- inflammatory effects in host cells we measured protein synthesis, NF-κB activation and KC (mouse IL-8) and IL-6 mRNA and protein secretion in wild type (WT) mouse embryonic fibroblasts (MEF). To test the role of the ER stress inducer PERK we compared these responses in PERK−/− and PERK-corrected PERK−/− MEF. During 4 hr treatments of WT MEF, HSL-C12 potentially activated NF-κB p65 by preventing the re-synthesis of IκB and increased transcription of KC and IL-6 genes (qPCR). HSL-C12 also inhibited secretion of KC and/or IL-6 into the media (ELISA) both in control conditions and also during stimulation by TNFα. HSL-C12 also activated PERK (as shown by increased phosphorylation of eI-F2α) and inhibited protein synthesis (as measured by incorporation of 35S-methionine by MEF). Comparisons of PERK−/− and PERK- corrected MEF showed that HSL-C12’s effects were explained in part by activation of PERK → phosphorylation of eI-F2α → inhibition of protein synthesis → reduced IκBα production → activation of NF-κB → increased transcription of the KC gene but reduced translation and secretion of KC. HSL-C12 may be an important modulator of early (up to 4 hrs) inflammatory signaling in P. aeruginosa infections

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Authors

  • M. A. Grabiner

  • Z. Fu

  • T. Wu

  • K. C. Barry

  • C. Schwarzer

  • T. E. Machen

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