Increased ERK signalling promotes inflammatory signalling in primary airway epithelial cells expressing Z ?1-antitrypsin.

ABSTRACT: Overexpression of Z ?1-antitrypsin is known to induce polymer formation, prime the cells for endoplasmic reticulum stress and initiate nuclear factor kappa B (NF-?B) signalling. However, whether endogenous expression in primary bronchial epithelial cells has similar consequences remains unclear. Moreover, the mechanism of NF-?B activation has not yet been elucidated. Here, we report excessive NF-?B 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-?B signalling in airway-derived cells represents a loss of anti-inflammatory signalling by M ?1-antitrypsin. Treatment of ZZ primary bronchial epithelial cells with purified plasma M ?1-antitrypsin attenuates this inflammatory response, opening up new therapeutic options to modulate airway inflammation in the lung.

SUBMITTER: van 't Wout EF 

PROVIDER: S-EPMC4007119 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature