Abstract
Overexpression of Z α1-antitrypsin is known to induce polymer formation, prime the cells for endoplasmic reticulum stress and initiate nuclear factor kappa B (NF-κB) signalling. However, whether endogenous expression in primary bronchial epithelial cells has similar consequences remains unclear. Moreover, the mechanism of NF-κB activation has not yet been elucidated. Here, we report excessive NF-κB signalling in resting primary bronchial epithelial cells from ZZ patients compared with wild-type (MM) controls, and this appears to be mediated by mitogen-activated protein/extracellular signal-regulated kinase, EGF receptor and ADAM17 activity. Moreover, we show that rather than being a response to protein polymers, NF-κB signalling in airway-derived cells represents a loss of anti-inflammatory signalling by M α1-antitrypsin. Treatment of ZZ primary bronchial epithelial cells with purified plasma M α1-antitrypsin attenuates this inflammatory response, opening up new therapeutic options to modulate airway inflammation in the lung.
Highlights
Alpha1-antitrypsin is a 52-kDa serine protease inhibitor, primarily produced by hepatocytes, and secreted locally by lung epithelial cells and alveolar macrophages [1,2]
We report excessive nuclear factor kappa B (NF-kB) signalling in resting primary bronchial epithelial cells from ZZ patients compared with wild-type (MM) controls, and this appears to be mediated by mitogen-activated protein/extracellular signal-regulated kinase, Epidermal growth factor (EGF) receptor and ADAM17 activity
We report here the detection of NF-kB activation in primary bronchial epithelial cells isolated from patients homozygous for the Z mutation (ZZ) and demonstrate this to be mediated by increased ADAM17-dependent EGF receptor (EGFR)–mitogen-activated protein/extracellular signal-regulated kinase (MEK)–ERK signalling in the absence of either detectable polymer formation or endoplasmic reticulum (ER) stress response
Summary
Alpha1-antitrypsin is a 52-kDa serine protease inhibitor (or serpin), primarily produced by hepatocytes, and secreted locally by lung epithelial cells and alveolar macrophages [1,2]. The Z mutation (E342K) of a1-antitrypsin causes subtle misfolding of the protein that permits polymer formation and accumulation within the endoplasmic reticulum (ER) of hepatocytes or degradation by the proteasome leading to deficiency of the secreted protein [8,9]. This causes hepatic cirrhosis through toxic gain-of-function within the liver, most likely due to the retention of polymers, and early-onset lung emphysema, due in large part to the loss of protease inhibition [10]. The discovery of polymers in broncho-alveolar lavage fluid and pulmonary tissue [11,12], the pro-inflammatory nature of such extracellular polymers [11,13] and their identification many years after liver transplantation [14] led to the proposal that pulmonary pathology could be induced by polymer-induced toxic gain-of-function with inflammation as an additional mechanism [15]
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