Cargando…

N-Terminal Region of Gelsolin Induces Apoptosis of Activated Hepatic Stellate Cells by a Caspase-Dependent Mechanism

Activated hepatic stellate cells (HSCs) are the major source for alteration of extracellular matrix in fibrosis and cirrhosis. Conditioned medium (CM) collected from immortalized human hepatocytes (IHH) have earlier been shown to be responsible for apoptosis of HSCs. In this study, we have shown tha...

Descripción completa

Detalles Bibliográficos
Autores principales: Mazumdar, Budhaditya, Meyer, Keith, Ray, Ranjit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430645/
https://www.ncbi.nlm.nih.gov/pubmed/22952982
http://dx.doi.org/10.1371/journal.pone.0044461
_version_ 1782241969779507200
author Mazumdar, Budhaditya
Meyer, Keith
Ray, Ranjit
author_facet Mazumdar, Budhaditya
Meyer, Keith
Ray, Ranjit
author_sort Mazumdar, Budhaditya
collection PubMed
description Activated hepatic stellate cells (HSCs) are the major source for alteration of extracellular matrix in fibrosis and cirrhosis. Conditioned medium (CM) collected from immortalized human hepatocytes (IHH) have earlier been shown to be responsible for apoptosis of HSCs. In this study, we have shown that antibodies raised against a peptide derived from a linear B-cell epitope in the N-terminal region of gelsolin identified a gelsolin fragment in IHH CM. Analysis of activated stellate cell death by CM collected from Huh7 cells transfected with plasmids encoding gelsolin deletion mutants suggested that the N-terminal half of gelsolin contained sequences which were responsible for stellate cell death. Further analysis determined that this activity was restricted to a region encompassing amino acids 1–70 in the gelsolin sequence; antibody directed to an epitope within this region was able to neutralize stellate cell death. Gelsolin modulation of cell death using this fragment involved upregulation of TRAIL-R1 and TRAIL-R2, and involved caspase 3 activation by extrinsic pathway. The apoptotic activity of N-terminal gelsolin fragments was restricted to activated but not quiescent stellate cells indicating its potential application in therapeutic use as an anti-fibrotic agent. Gelsolin fragments encompassing N-terminal regions in polypeptides of different molecular sizes were detected by N-terminal peptide specific antiserum in IHH CM immunoprecipitated with chronically HCV infected patient sera, suggesting the presence of autoantibodies generated against N-terminal gelsolin fragments in patients with chronic liver disease.
format Online
Article
Text
id pubmed-3430645
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-34306452012-09-05 N-Terminal Region of Gelsolin Induces Apoptosis of Activated Hepatic Stellate Cells by a Caspase-Dependent Mechanism Mazumdar, Budhaditya Meyer, Keith Ray, Ranjit PLoS One Research Article Activated hepatic stellate cells (HSCs) are the major source for alteration of extracellular matrix in fibrosis and cirrhosis. Conditioned medium (CM) collected from immortalized human hepatocytes (IHH) have earlier been shown to be responsible for apoptosis of HSCs. In this study, we have shown that antibodies raised against a peptide derived from a linear B-cell epitope in the N-terminal region of gelsolin identified a gelsolin fragment in IHH CM. Analysis of activated stellate cell death by CM collected from Huh7 cells transfected with plasmids encoding gelsolin deletion mutants suggested that the N-terminal half of gelsolin contained sequences which were responsible for stellate cell death. Further analysis determined that this activity was restricted to a region encompassing amino acids 1–70 in the gelsolin sequence; antibody directed to an epitope within this region was able to neutralize stellate cell death. Gelsolin modulation of cell death using this fragment involved upregulation of TRAIL-R1 and TRAIL-R2, and involved caspase 3 activation by extrinsic pathway. The apoptotic activity of N-terminal gelsolin fragments was restricted to activated but not quiescent stellate cells indicating its potential application in therapeutic use as an anti-fibrotic agent. Gelsolin fragments encompassing N-terminal regions in polypeptides of different molecular sizes were detected by N-terminal peptide specific antiserum in IHH CM immunoprecipitated with chronically HCV infected patient sera, suggesting the presence of autoantibodies generated against N-terminal gelsolin fragments in patients with chronic liver disease. Public Library of Science 2012-08-29 /pmc/articles/PMC3430645/ /pubmed/22952982 http://dx.doi.org/10.1371/journal.pone.0044461 Text en © 2012 Mazumdar et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Mazumdar, Budhaditya
Meyer, Keith
Ray, Ranjit
N-Terminal Region of Gelsolin Induces Apoptosis of Activated Hepatic Stellate Cells by a Caspase-Dependent Mechanism
title N-Terminal Region of Gelsolin Induces Apoptosis of Activated Hepatic Stellate Cells by a Caspase-Dependent Mechanism
title_full N-Terminal Region of Gelsolin Induces Apoptosis of Activated Hepatic Stellate Cells by a Caspase-Dependent Mechanism
title_fullStr N-Terminal Region of Gelsolin Induces Apoptosis of Activated Hepatic Stellate Cells by a Caspase-Dependent Mechanism
title_full_unstemmed N-Terminal Region of Gelsolin Induces Apoptosis of Activated Hepatic Stellate Cells by a Caspase-Dependent Mechanism
title_short N-Terminal Region of Gelsolin Induces Apoptosis of Activated Hepatic Stellate Cells by a Caspase-Dependent Mechanism
title_sort n-terminal region of gelsolin induces apoptosis of activated hepatic stellate cells by a caspase-dependent mechanism
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430645/
https://www.ncbi.nlm.nih.gov/pubmed/22952982
http://dx.doi.org/10.1371/journal.pone.0044461
work_keys_str_mv AT mazumdarbudhaditya nterminalregionofgelsolininducesapoptosisofactivatedhepaticstellatecellsbyacaspasedependentmechanism
AT meyerkeith nterminalregionofgelsolininducesapoptosisofactivatedhepaticstellatecellsbyacaspasedependentmechanism
AT rayranjit nterminalregionofgelsolininducesapoptosisofactivatedhepaticstellatecellsbyacaspasedependentmechanism