Mediator generation and signaling events in alveolar epithelial cells attacked by S. aureus alpha-toxin

• Published in: American journal of physiology. Lung cellular and molecular physiology 2002-02, Vol.282 (2), p.L207-L214
• Main Authors: Rose, Frank, Dahlem, Gabriele, Guthmann, Bernd, Grimminger, Friedrich, Maus, Ulrich, Hänze, Jörg, Duemmer, Nils, Grandel, Ulrich, Seeger, Werner, Ghofrani, Hossein Ardeschir
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Toxins - pharmacology; Cell Line; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Hemolysin Proteins - pharmacology; Inflammation Mediators - metabolism; Inositol Phosphates - metabolism; Interleukin-6 - metabolism; Interleukin-8 - genetics; Interleukin-8 - metabolism; Male; Pneumonia - immunology; Pneumonia - metabolism; Pneumonia - microbiology; Pulmonary Alveoli - cytology; Pulmonary Alveoli - immunology; Pulmonary Alveoli - microbiology; Rats; Rats, Sprague-Dawley; RNA, Messenger - analysis; Sepsis - immunology; Sepsis - metabolism; Sepsis - microbiology; Signal Transduction - immunology; Staphylococcus aureus
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00156.2001

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.