A20 inhibits toll-like receptor 2- and 4-mediated interleukin-8 synthesis in airway epithelial cells

Am J Respir Cell Mol Biol. 2004 Sep;31(3):330-6. doi: 10.1165/rcmb.2003-0438OC. Epub 2004 May 13.

Abstract

The zinc finger protein A20 is encoded by an immediate early response gene and acts as an inhibitor of nuclear factor (NF)-kappaB-dependent gene expression induced by different stimuli, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). Toll-like receptor 2 (TLR2) and TLR4 have been found to transduce, respectively, peptidoglycan (PGN) and lipopolysaccharide (LPS) signals for the activation of NF-kappaB and the production of inflammatory cytokines. Here, we have examined the role of A20 in TLR-mediated NF-kappaB-dependent gene expression in human airway epithelial cells (AECs). Stimulation with LPS and PGN resulted in a significant increase in the level of A20 mRNA in primary cultured AECs and in NCI-H292 AECs. LPS and PGN induced activation of the IL-8 promoter both in NCI-H292 AECs and in HEK293 cells expressing either TLR2 or TLR4 plus MD-2. Dominant-negative myeloid differentiation protein and a mutant form of IkappaBalpha attenuated this PGN- or LPS-induced activation of the IL-8 promoter. Furthermore, overexpression of A20 inhibited activation of both NF-kappaB and the IL-8 promoter by PGN or LPS in these cells. Taken together, our results suggest that A20 may function as a negative regulator of TLR-mediated inflammatory responses in the airway, thereby protecting the host against harmful overresponses to pathogens.

MeSH terms

  • Antigens, Surface / genetics
  • Cell Line
  • DNA-Binding Proteins
  • Humans
  • I-kappa B Proteins / drug effects
  • I-kappa B Proteins / metabolism
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / genetics
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Antigen 96
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / metabolism*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Nuclear Proteins
  • Peptidoglycan / pharmacology
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • Proteins / genetics
  • Proteins / physiology*
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / metabolism*
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / immunology*
  • Respiratory Mucosa / metabolism*
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • Antigens, Surface
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Interleukin-8
  • Intracellular Signaling Peptides and Proteins
  • LY96 protein, human
  • Lipopolysaccharides
  • Lymphocyte Antigen 96
  • Membrane Glycoproteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nuclear Proteins
  • Peptidoglycan
  • Proteins
  • RNA, Messenger
  • Receptors, Cell Surface
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • NF-KappaB Inhibitor alpha
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3