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Increased ERK signalling promotes inflammatory signalling in primary airway epithelial cells expressing Z α1-antitrypsin.

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van 't Wout, Emily FA 
Dickens, Jennifer A 
van Schadewijk, Annemarie 
Haq, Imran 
Kwok, Hang Fai 


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.



ADAM Proteins, ADAM17 Protein, Cell Line, Tumor, Cytokines, Endoplasmic Reticulum Stress, Epithelial Cells, ErbB Receptors, Humans, Inflammation Mediators, Lung, MAP Kinase Signaling System, Mutation, Missense, NF-kappa B, Primary Cell Culture, Protein Multimerization, Protein Processing, Post-Translational, Signal Transduction, alpha 1-Antitrypsin

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Hum Mol Genet

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Oxford University Press (OUP)
Medical Research Council (G1000277)
Medical Research Council (G1002610)
Medical Research Council (G0901786)
Medical Research Council (G0601840)
Wellcome Trust (100140/Z/12/Z)