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

Hdl Handle:
http://hdl.handle.net/10147/127130
Title:
Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency.
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
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)
Issue Date:
15-Apr-2010
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
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
ISSN:
1550-6606

Full metadata record

DC FieldValue Language
dc.contributor.authorCarroll, Tomás Pen
dc.contributor.authorGreene, Catherine Men
dc.contributor.authorO'Connor, Catherine Aen
dc.contributor.authorNolan, Aine Men
dc.contributor.authorO'Neill, Shane Jen
dc.contributor.authorMcElvaney, Noel Gen
dc.date.accessioned2011-04-05T10:09:18Z-
dc.date.available2011-04-05T10:09:18Z-
dc.date.issued2010-04-15-
dc.identifier.citationEvidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency. 2010, 184 (8):4538-46 J. Immunol.en
dc.identifier.issn1550-6606-
dc.identifier.pmid20228200-
dc.identifier.doi10.4049/jimmunol.0802864-
dc.identifier.urihttp://hdl.handle.net/10147/127130-
dc.description.abstractThe 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.-
dc.language.isoenen
dc.subject.meshAmino Acid Substitution-
dc.subject.meshCells, Cultured-
dc.subject.meshChild-
dc.subject.meshCytokines-
dc.subject.meshEndoplasmic Reticulum-
dc.subject.meshFemale-
dc.subject.meshGene Expression Regulation-
dc.subject.meshHumans-
dc.subject.meshIntracellular Space-
dc.subject.meshMale-
dc.subject.meshMonocytes-
dc.subject.meshOxidative Stress-
dc.subject.meshProtein Folding-
dc.subject.meshYoung Adult-
dc.subject.meshalpha 1-Antitrypsin-
dc.subject.meshalpha 1-Antitrypsin Deficiency-
dc.titleEvidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency.en
dc.typeArticleen
dc.contributor.departmentRespiratory Research Division, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland. tcarroll@rcsi.ieen
dc.identifier.journalJournal of immunology (Baltimore, Md. : 1950)en
dc.description.provinceLeinster-

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