title: Reduced surface toll-like receptor-4 expression and absent interferon-γ-inducible protein-10 induction in cystic fibrosis airway cells.
abstract: ABSTRACT As part of the innate and adaptive immune system, airway epithelial cells secrete proinflammatory cytokines after activation of Toll-like receptors (TLRs) by pathogens. Nevertheless, cystic fibrosis (CF) airways are chronically infected with Pseudomonas aeruginosa, suggesting a modified immune response in CF. The authors have shown that in CF bronchial epithelial cells, a reduced surface expression of TLR-4 causes a diminished interleukin (IL)-8 and IL-6 response upon lipopolysaccharide (LPS) stimulation. However, there is no information regarding activation of the MyD88 (myeloid differentiation primary response gene 88)-independent TLR-4 signaling pathway by LPS, which results in the activation of adaptive immune responses by secretion of the T cell-recruiting chemokine interferon-γ-inducible protein (IP)-10. Therefore, the authors investigated the induction of IP-10 in CF bronchial epithelial cell line CFBE41o- and its CFTR-corrected isotype under well-differentiating conditions. TLR-4 surface expression was significantly reduced in CFBE41o- by a factor of 2, compared to the CFTR-corrected cells. In CFTR-corrected cells, stimulation with LPS increased IP-10 secretion. Incubating cells with siRNA directed against TLR-4 inhibited the LPS stimulated increase of IP-10 in CFTR-corrected cells. The reduced TLR-4 surface expression in CF cells causes the loss of induction of IP-10 by LPS. This could compromise adaptive immune responses in CF due to a reduced T-cell recruitment.
authors.affiliation: Department of Pulmonary Medicine, Philipps-University Marburg, Marburg, Germany.
authors.forename: Gerrit
authors.initials: G
authors.lastname: John
authors.forename: Shashi
authors.initials: S
authors.lastname: Chillappagari
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Rubin
authors.forename: Dieter C
authors.initials: DC
authors.lastname: Gruenert
authors.forename: Markus O
authors.initials: MO
authors.lastname: Henke
mesh_terms: D002460:Cell Line; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D003550:Cystic Fibrosis / Q000276:immunology / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012137:Respiratory System / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma