Oncostatin M and TNF-α Induce Alpha-1 Antitrypsin Production in Undifferentiated Adipose Stromal Cells

Abstract

Alpha-1 antitrypsin (A1AT), a circulating acute-phase reactant antiprotease, is produced and secreted by cells of endodermal epithelial origin, primarily hepatocytes, and by immune cells. Deficiency of A1AT is associated with increased risk of excessive lung inflammation and injury, especially following chronic cigarette smoke (CS) exposure. Exogenous administration of mesenchymal progenitor cells, including adipose tissue-derived stromal/stem cells (ASC), alleviates CS-induced lung injury through paracrine effectors such as growth factors. It is unknown, however, if mesodermal ASC can secrete functional A1AT and if CS exposure affects their A1AT production. Human ASC collected via liposuction from nonsmoking or smoking donors were stimulated by inflammatory cytokines tumor necrosis alpha (TNFα), oncostatin M (OSM), and/or dexamethasone (DEX) or were exposed to sublethal concentrations of ambient air control or CS extract (0.5%-2%). We detected minimal expression and secretion of A1AT by cultured ASC during unstimulated conditions, which significantly increased following stimulation with TNFα or OSM. Furthermore, TNFα and OSM synergistically enhanced A1AT expression and secretion, which were further increased by DEX. The A1AT transcript variant produced by stimulated ASC resembled that produced by bronchial epithelial cells rather than the variant produced by monocytes/macrophages. While the cigarette smoking status of the ASC donor had no measurable effect on the ability of ASC to induce A1AT expression, active exposure to CS extract markedly reduced A1AT expression and secretion by cultured ASC, as well as human tracheobronchial epithelial cells. ASC-secreted A1AT covalently complexed with neutrophil elastase in control ASC, but not in cells transfected with A1AT siRNA. Undifferentiated ASC may require priming to secrete functional A1AT, a potent antiprotease that may be relevant to stem cell therapeutic effects.

Updates in the Management of Alpha-1 Antitrypsin Deficiency Lung Disease

“…48 In the era of regenerative medicine, we and others have shown that the adipose-derived mesenchymal stem cell (MSC)secretome contains AAT with high anti-elastase in vitro activity and other proteins involved in protease/anti-protease balance. 49,50 These findings position allogenic MSC as a novel therapeutic option for AATD patients.…”

Alpha-1-antitrypsin binds to the glucocorticoid receptor with biological significance in macrophages

“…GR signaling in response to GC leads to both anti-inflammatory effects and immune suppression. A known connection between AAT and GR is that GR activation by GC increases AAT production at the transcriptional level (Kadiyala et al , 2016; Ni et al , 2017).…”

<p>Alpha-1 Antitrypsin Induces Epithelial-to-Mesenchymal Transition, Endothelial-to-Mesenchymal Transition, and Drug Resistance in Lung Cancer Cells</p>

“…9 Alpha-1-antitrypsin (A1AT) belongs to the serpin superfamily of proteins and is produced and secreted by cells of endodermal epithelial origin, primarily hepatocytes, and immune cells. It plays important roles in many diseases such as liver disease, emphysema, polyangiitis, and lung diseases [10][11][12][13][14][15] as an anti-protease, anti-inflammatory, and anti-apoptotic agent. 16 Recent studies indicate that A1AT is a key factor in epithelial-to-mesenchymal transition (EMT) in lung cancer.…”