title: α₁-Antitrypsin modulates lung endothelial cell inflammatory responses to TNF-α.
abstract: α₁-Antitrypsin (A1AT) is an acute-phase reactant, but also a major protective factor against the development of chronic obstructive pulmonary disease, a complex disease with sustained chronic inflammation. The lung-protective effects of A1AT have been attributed to the inhibition of proteases involved in lung matrix fragmentation, macrophage activation, and endothelial-cell apoptosis. More recently, A1AT has been shown to directly interact with or modulate the actions of cytokines such as TNF-α or IL-1 in inflammatory cells, but its effect on the lung endothelium, an active participant in the amplification and resolution of inflammation, has received little attention. An important role of A1AT in modulating lung endothelial inflammatory responses is expected, given the high concentrations of circulating A1AT during inflammation and its active uptake by endothelial cells. We investigated the role of A1AT in primary lung microvascular endothelial cell activation by relevant cytokines such as TNF-α or IL-1β. Despite an initial marked augmentation of TNF-α self-induced transcription, A1AT inhibited TNF-α receptor 1 up-regulation and significantly reduced TNF-α secretion, effects that were associated with inhibition of TNF-α-converting enzyme activity. Furthermore, A1AT inhibited calpain activity, whose activation by TNF-α contributed to decreased intracellular A1AT concentrations. These data indicate that A1AT initially facilitates acute responses of the endothelium to TNF-α, followed by selective inhibition of TNF-α-induced-self amplification, which may assist the vasculature in the resolution of chronic inflammation.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, Center for Immunobiology, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Angelia D
authors.initials: AD
authors.lastname: Lockett
authors.forename: Samuel
authors.initials: S
authors.lastname: Kimani
authors.forename: Godfrey
authors.initials: G
authors.lastname: Ddungu
authors.forename: Sabine
authors.initials: S
authors.lastname: Wrenger
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.forename: Sabina M
authors.initials: SM
authors.lastname: Janciauskiene
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D002154:Calpain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D020672:I-kappa B Proteins / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D061251:Primary Cell Culture; D059748:Proteolysis; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; C052994:interleukin-1beta (163-171); D000072000:NF-KappaB Inhibitor alpha; D002154:Calpain; D051722:ADAM Proteins; D000072198:ADAM17 Protein