title: Alveolar epithelium down-modulates endotoxin-but not tumor necrosis factor alpha-induced activation of endothelium and selectively inhibits neutrophil transendothelial migration.
abstract: In a previous study, the authors reported the development of an optimized model bilayer of endothelium with alveolar epithelium using A549 cells, and that neutrophil transendothelial migration across endotoxin (lipopolysaccharide [LPS])-activated endothelial cells was attenuated by the apposition of the epithelium. Here the authors investigated whether this modulation by the epithelium extended to other stimuli such as tumor necrosis factor (TNF)-alpha, which, like LPS, activates proinflammatory gene transcription via nuclear factor (NF)-kappa B-dependent mechanisms to induce neutrophil transendothelial migration. Unlike the response to LPS, neutrophil migration in response to TNF-alpha was not altered by the presence of lung epithelial cells, except at a low concentration of TNF-alpha upon alveolar directional exposure of the endothelium, i.e., from the epithelial side of the bilayer. Epithelial cells in the bilayer reduced expression of E-selectin on the endothelium in response to LPS, but not with TNF-alpha stimulation. The production of the chemokine CXCL8 was also differentially modulated by epithelium in response to these 2 mediators. The expression of Toll-like receptor 4 (TLR4), which is involved in LPS recognition by endothelium, was not altered by epithelial cells, suggesting that the anti-inflammatory effect on endothelium may be via downstream LPS-induced signaling events. Inhibition of some candidate anti-inflammatory mediators produced by epithelium, such as nitric oxide, or the activity of interleukin (IL)-10 or transforming growth factor (TGF)-beta had no effect on the inhibitory influence of the epithelium in the bilayers. The authors' findings demonstrate a selective role for alveolar epithelial cells, via either direct cell-cell contact or yet-to-be-identified but short-range or short-lived product(s) in attenuating endothelial responses to endotoxin.
authors: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. Andrew.Issekutz@iwk.nshealth.ca
authors: Amy
authors: A
authors: Weppler
authors: Andrew C
authors: AC
authors: Issekutz
mesh_terms: D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000276:immunology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D036904:Leukocyte Rolling; D008070:Lipopolysaccharides / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology*; D011650:Pulmonary Alveoli / Q000276:immunology*; D011994:Recombinant Proteins / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; D015815:Cell Adhesion Molecules; D016209:Interleukin-8; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4