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

van 't Wout EF, Dickens JA, van Schadewijk A, Haq I, Kwok HF, Ordóñez A, Murphy G, Stolk J, Lomas DA, Hiemstra PS, Marciniak SJ - Hum. Mol. Genet. (2013)

Bottom Line: 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.Moreover, the mechanism of NF-κB activation has not yet been elucidated.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.

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.

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ZZ primary bronchial epithelial cells show an enhanced inflammatory response dependent of the ERK/EGFR/ADAM17 pathway. Impaired expression of α1-antitrypsin in primary bronchial epithelial cells leads to increased phosphorylation of ERK1/2, which is dependent on MEK, EGFR and ADAM17. M α1-antitrypsin modulates this inflammatory response via a yet undefined mechanism.
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DDT487F6: ZZ primary bronchial epithelial cells show an enhanced inflammatory response dependent of the ERK/EGFR/ADAM17 pathway. Impaired expression of α1-antitrypsin in primary bronchial epithelial cells leads to increased phosphorylation of ERK1/2, which is dependent on MEK, EGFR and ADAM17. M α1-antitrypsin modulates this inflammatory response via a yet undefined mechanism.

Mentions: Taken together, these data indicate that the increased NF-κB signalling in ZZ primary bronchial epithelial cells is caused by phosphorylation of ERK1/2. This is due to increased availability of ADAM17-dependent EGFR ligands leading to activation of the EGFR and signalling via MEK (Fig. 6). Surprisingly, we were unable to detect the formation of polymers of α1-antitrypsin in ZZ primary bronchial epithelial cells or A549 lung adenocarcinoma cells overexpressing the protein, which may reflect the low levels of α1-antitrypsin expression of which these cells are capable.Figure 6.


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

van 't Wout EF, Dickens JA, van Schadewijk A, Haq I, Kwok HF, Ordóñez A, Murphy G, Stolk J, Lomas DA, Hiemstra PS, Marciniak SJ - Hum. Mol. Genet. (2013)

ZZ primary bronchial epithelial cells show an enhanced inflammatory response dependent of the ERK/EGFR/ADAM17 pathway. Impaired expression of α1-antitrypsin in primary bronchial epithelial cells leads to increased phosphorylation of ERK1/2, which is dependent on MEK, EGFR and ADAM17. M α1-antitrypsin modulates this inflammatory response via a yet undefined mechanism.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4007119&req=5

DDT487F6: ZZ primary bronchial epithelial cells show an enhanced inflammatory response dependent of the ERK/EGFR/ADAM17 pathway. Impaired expression of α1-antitrypsin in primary bronchial epithelial cells leads to increased phosphorylation of ERK1/2, which is dependent on MEK, EGFR and ADAM17. M α1-antitrypsin modulates this inflammatory response via a yet undefined mechanism.
Mentions: Taken together, these data indicate that the increased NF-κB signalling in ZZ primary bronchial epithelial cells is caused by phosphorylation of ERK1/2. This is due to increased availability of ADAM17-dependent EGFR ligands leading to activation of the EGFR and signalling via MEK (Fig. 6). Surprisingly, we were unable to detect the formation of polymers of α1-antitrypsin in ZZ primary bronchial epithelial cells or A549 lung adenocarcinoma cells overexpressing the protein, which may reflect the low levels of α1-antitrypsin expression of which these cells are capable.Figure 6.

Bottom Line: 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.Moreover, the mechanism of NF-κB activation has not yet been elucidated.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus