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.

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

“…(25) Antiinflammatory actions of A1AT as well as FAs in neutrophils have previously been observed. (5,6,(26)(27)(28) For example, short-chain FAs reduced TNF-α production by lipopolysaccharide (LPS)-stimulated human neutrophils, (29) and also inhibited the expression of TNF-α and NO in rat neutrophils via attenuation of NF-κB activation. (30) Polyunsaturated FAs have and nuclear fractions were analyzed by electrophoresis and western blot.…”

α 1-antitrypsin modulates microglial-mediated neuroinflammation and protects microglial cells from amyloid-β-induced toxicity

“…Recently, a new anti-inflammatory role for α 1 -antitrypsin (A1AT) has been described for activated monocytes as well as for lung endothelial cells [11,12]. The serine protease inhibitory activity mediated by A1AT protein is well acknowledged for its essential role in the degradation of neutrophil elastase in the lung [13].…”

Alpha-1 Antitrypsin Augmentation Therapy Corrects Accelerated Neutrophil Apoptosis in Deficient Individuals

“…Taken together, these results show that TNF-a release and membrane expression are increased in ZZ-AATD and that TNF-a is removed from the cell surface by increased ADAM-17 activity. These observations can be explained by two linked mechanisms supported by recent literature, as follows: first, ER stress can induce TNF-a release (40), and second, increased ADAM-17 activity leads to increased cleavage of mTNF-a to sTNF-a from neutrophils (41). The net effect of these two processes is increased sTNF-a release.…”