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    Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency.

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    Authors
    Carroll, Tomás P
    Greene, 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.ie
    Issue Date
    2010-04-15
    MeSH
    Amino Acid Substitution
    Cells, 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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    Citation
    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)
    URI
    http://hdl.handle.net/10147/127130
    DOI
    10.4049/jimmunol.0802864
    PubMed ID
    20228200
    Abstract
    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
    Article
    Language
    en
    ISSN
    1550-6606
    ae974a485f413a2113503eed53cd6c53
    10.4049/jimmunol.0802864
    Scopus Count
    Collections
    Beaumont Hospital

    entitlement

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