Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency.
Authors
Carroll, Tomás PGreene, Catherine M
O'Connor, Catherine A
Nolan, Aine M
O'Neill, Shane J
McElvaney, Noel G
Affiliation
Respiratory Research Division, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland. tcarroll@rcsi.ieIssue Date
2010-04-15MeSH
Amino Acid SubstitutionCells, Cultured
Child
Cytokines
Endoplasmic Reticulum
Female
Gene Expression Regulation
Humans
Intracellular Space
Male
Monocytes
Oxidative Stress
Protein Folding
Young Adult
alpha 1-Antitrypsin
alpha 1-Antitrypsin Deficiency
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Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency. 2010, 184 (8):4538-46 J. Immunol.Journal
Journal of immunology (Baltimore, Md. : 1950)DOI
10.4049/jimmunol.0802864PubMed ID
20228200Abstract
The hereditary disorder alpha-1 antitrypsin (AAT) deficiency results from mutations in the SERPINA1 gene and presents with emphysema in young adults and liver disease in childhood. The most common form of AAT deficiency occurs because of the Z mutation, causing the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER). This leads to ER stress and contributes significantly to the liver disease associated with the condition. In addition to hepatocytes, AAT is also synthesized by monocytes, neutrophils, and epithelial cells. In this study we show for the first time that the unfolded protein response (UPR) is activated in quiescent monocytes from ZZ individuals. Activating transcription factor 4, X-box binding protein 1, and a subset of genes involved in the UPR are increased in monocytes from ZZ compared with MM individuals. This contributes to an inflammatory phenotype with ZZ monocytes exhibiting enhanced cytokine production and activation of the NF-kappaB pathway when compared with MM monocytes. In addition, we demonstrate intracellular accumulation of AAT within the ER of ZZ monocytes. These are the first data showing that Z AAT protein accumulation induces UPR activation in peripheral blood monocytes. These findings change the current paradigm regarding lung inflammation in AAT deficiency, which up until now was derived from the protease-anti-protease hypothesis, but which now must include the exaggerated inflammatory response generated by accumulated aberrantly folded AAT in circulating blood cells.Item Type
ArticleLanguage
enISSN
1550-6606ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.0802864
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