TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells.

  • Greene C
  • Carroll T
  • Smith S
 et al. 
  • 32

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Abstract

Cystic fibrosis (CF) is a genetic disease characterized by severe neutrophil-dominated airway inflammation. An important cause of inflammation in CF is Pseudomonas aeruginosa infection. We have evaluated the importance of a number of P. aeruginosa components, namely lipopeptides, LPS, and unmethylated CpG DNA, as proinflammatory stimuli in CF by characterizing the expression and functional activity of their cognate receptors, TLR2/6 or TLR2/1, TLR4, and TLR9, respectively, in a human tracheal epithelial line, CFTE29o(-), which is homozygous for the DeltaF508 CF transmembrane conductance regulator mutation. We also characterized TLR expression and function in a non-CF airway epithelial cell line 16HBE14o(-). Using RT-PCR, we demonstrated TLR mRNA expression. TLR cell surface expression was assessed by fluorescence microscopy. Lipopeptides, LPS, and unmethylated CpG DNA induced IL-8 and IL-6 protein production in a time- and dose-dependent manner. The CF and non-CF cell lines were largely similar in their TLR expression and relative TLR responses. ICAM-1 expression was also up-regulated in CFTE29o(-) cells following stimulation with each agonist. CF bronchoalveolar lavage fluid, which contains LPS, bacterial DNA, and neutrophil elastase (a neutrophil-derived protease that can activate TLR4), up-regulated an NF-kappaB-linked reporter gene and increased IL-8 protein production in CFTE29o(-) cells. This effect was abrogated by expression of dominant-negative versions of MyD88 or Mal, key signal transducers for TLRs, thereby implicating them as potential anti-inflammatory agents for CF.

Author-supplied keywords

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Antigens, Differentiation: genetics
  • Antigens, Differentiation: physiology
  • Bacterial Proteins
  • Bacterial Proteins: antagonists & inhibitors
  • Bacterial Proteins: pharmacology
  • Bronchoalveolar Lavage Fluid
  • Bronchoalveolar Lavage Fluid: immunology
  • Cell Line
  • CpG Islands
  • CpG Islands: physiology
  • Cystic Fibrosis
  • Cystic Fibrosis: immunology
  • Cystic Fibrosis: microbiology
  • Cystic Fibrosis: pathology
  • Humans
  • Inflammation Mediators
  • Inflammation Mediators: agonists
  • Inflammation Mediators: physiology
  • Intercellular Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1: biosynthesis
  • Interleukin-6
  • Interleukin-6: biosynthesis
  • Interleukin-8
  • Interleukin-8: antagonists & inhibitors
  • Interleukin-8: biosynthesis
  • Lipopeptides
  • Lipopolysaccharides
  • Lipopolysaccharides: antagonists & inhibitors
  • Lipopolysaccharides: pharmacology
  • Lipoproteins
  • Lipoproteins: antagonists & inhibitors
  • Lipoproteins: pharmacology
  • Membrane Glycoproteins
  • Membrane Glycoproteins: agonists
  • Membrane Glycoproteins: biosynthesis
  • Membrane Glycoproteins: pharmacology
  • Membrane Glycoproteins: physiology
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • NF-kappa B: antagonists & inhibitors
  • NF-kappa B: biosynthesis
  • NF-kappa B: genetics
  • Oligodeoxyribonucleotides
  • Oligodeoxyribonucleotides: pharmacology
  • Oligopeptides
  • Oligopeptides: antagonists & inhibitors
  • Oligopeptides: pharmacology
  • Pseudomonas Infections
  • Pseudomonas Infections: immunology
  • Pseudomonas Infections: microbiology
  • Pseudomonas Infections: pathology
  • Receptors, Cell Surface
  • Receptors, Cell Surface: agonists
  • Receptors, Cell Surface: biosynthesis
  • Receptors, Cell Surface: physiology
  • Receptors, Immunologic
  • Receptors, Immunologic: genetics
  • Receptors, Immunologic: physiology
  • Receptors, Interleukin-1
  • Respiratory Mucosa
  • Respiratory Mucosa: immunology
  • Respiratory Mucosa: metabolism
  • Respiratory Mucosa: pathology
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • U937 Cells
  • Up-Regulation

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Authors

  • Catherine M Greene

  • Tomás P Carroll

  • Stephen G J Smith

  • Clifford C Taggart

  • James Devaney

  • Siobhan Griffin

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