title: A20 inhibits toll-like receptor 2- and 4-mediated interleukin-8 synthesis in airway epithelial cells.
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.
authors.affiliation: First Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Gon
authors.forename: Yasukiyo
authors.initials: Y
authors.lastname: Asai
authors.forename: Shu
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizumura
authors.forename: Itsuro
authors.initials: I
authors.lastname: Jibiki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Machino
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
authors.forename: Takashi
authors.initials: T
authors.lastname: Horie
mesh_terms: D000954:Antigens, Surface / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins; D010457:Peptidoglycan / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D000954:Antigens, Surface; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009687:Nuclear Proteins; D010457:Peptidoglycan; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000072000:NF-KappaB Inhibitor alpha; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3