title: Mediator generation and signaling events in alveolar epithelial cells attacked by S. aureus alpha-toxin.
abstract: Staphylococcus aureus alpha-toxin is a pore-forming bacterial exotoxin that has been implicated as a significant virulence factor in human staphylococcal diseases. In primary cultures of rat pneumocyte type II cells and the human A549 alveolar epithelial cell line, purified alpha-toxin provoked rapid-onset phosphatidylinositol (PtdIns) hydrolysis as well as liberation of nitric oxide and the prostanoids PGE(2), PGI(2), and thromboxane A(2). In addition, sustained upregulation of proinflammatory interleukin (IL)-8 mRNA expression and protein secretion occurred. "Priming" with low-dose IL-1beta markedly enhanced the IL-8 response to alpha-toxin, which was then accompanied by IL-6 appearance. The cytokine response was blocked by the intracellular Ca(2+)-chelating reagent 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, the protein kinase C inhibitor bis-indolyl maleimide I, as well as two independent inhibitors of nuclear factor-kappaB activation, pyrrolidine dithiocarbamate and caffeic acid phenethyl ester. We conclude that alveolar epithelial cells are highly reactive target cells of staphylococcal alpha-toxin. alpha-Toxin pore-associated transmembrane Ca(2+) flux and PtdIns hydrolysis-related signaling with downstream activation of protein kinase C and nuclear translocation of nuclear factor-kappaB are suggested to represent important underlying mechanisms. Such reactivity of the alveolar epithelial cells may be relevant for pathogenic sequelae in staphylococcal lung disease.
authors.affiliation: Department of Internal Medicine, Justus-Liebig University, Giessen D-35392, Germany. Frank.Rose@innere.med.uni-giessen.de
authors.forename: Frank
authors.initials: F
authors.lastname: Rose
authors.forename: Gabriele
authors.initials: G
authors.lastname: Dahlem
authors.forename: Bernd
authors.initials: B
authors.lastname: Guthmann
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Maus
authors.forename: Jörg
authors.initials: J
authors.lastname: Hänze
authors.forename: Nils
authors.initials: N
authors.lastname: Duemmer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grandel
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006460:Hemolysin Proteins / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D007295:Inositol Phosphates / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction / Q000276:immunology*; D013211:Staphylococcus aureus
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D018836:Inflammation Mediators; D007295:Inositol Phosphates; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; C021091:staphylococcal alpha-toxin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor