title: Role of Pneumococcal Autolysin for KLF4 Expression and Chemokine Secretion in Lung Epithelium.
abstract: In severe pneumococcal pneumonia, the delicate balance between a robust inflammatory response necessary to kill bacteria and the loss of organ function determines the outcome of disease. In this study, we tested the hypothesis that Krueppel-like factor (KLF) 4 may counter-regulate Streptococcus pneumoniae-related human lung epithelial cell activation using the potent proinflammatory chemokine IL-8 as a model molecule. Pneumococci induced KLF4 expression in human lung, in primary human bronchial epithelial cells, and in the lung epithelial cell line BEAS-2B. Whereas proinflammatory cell activation depends mainly on the classical Toll-like receptor 2-mitogen-activated protein kinase or phosphatidylinositide 3-kinase and NF-κB pathways, the induction of KLF4 occurred independently of these molecules but relied, in general, on tyrosine kinase activation and, in part, on the src kinase family member yamaguchi sarcoma viral oncogene homolog (yes) 1. The up-regulation of KLF4 depended on the activity of the main pneumococcal autolysin LytA. KLF4 overexpression suppressed S. pneumoniae-induced NF-κB and IL-8 reporter gene activation and release, whereas small interfering RNA-mediated silencing of KLF4 or yes1 kinase led to an increase in IL-8 release. The KLF4-dependent down-regulation of NF-κB luciferase activity could be rescued by the overexpression of the histone acetylase p300/cAMP response element-binding protein-associated factor. In conclusion, KLF4 acts as a counter-regulatory transcription factor in pneumococci-related proinflammatory activation of lung epithelial cells, thereby potentially preventing lung hyperinflammation and subsequent organ failure.
authors.affiliation: 1 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Zahlten
authors.affiliation: 1 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Herta
authors.affiliation: 1 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Kabus
authors.affiliation: 1 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Steinfeldt
authors.affiliation: 2 Department of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Olivia
authors.initials: O
authors.lastname: Kershaw
authors.affiliation: 3 Departamento de Microbiología Molecular, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain; and.|4 CIBER de Enfermedades Respiratorias, Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: García
authors.affiliation: 1 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Hocke
authors.affiliation: 2 Department of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.affiliation: 1 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ralf-Harto
authors.initials: RH
authors.lastname: Hübner
authors.affiliation: 1 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Steinicke
authors.affiliation: 1 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jan-Moritz
authors.initials: JM
authors.lastname: Doehn
authors.affiliation: 1 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.affiliation: 1 Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hippenstiel
mesh_terms: D001426:Bacterial Proteins / Q000502:physiology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D009238:N-Acetylmuramoyl-L-alanine Amidase / Q000502:physiology*; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D011401:Promoter Regions, Genetic; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000201:enzymology; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D016209:Interleukin-8; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D009238:N-Acetylmuramoyl-L-alanine Amidase
keywords: Streptococcus pneumoniae; inflammation; innate immunity; lung; pneumonia