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Electroporation-mediated transfer of plasmids to the lung results in reduced TLR9 signaling and inflammation

Electroporation can deliver DNA efficiently and safely to tissues in live animals, including the lung where it causes little inflammation or lung injury. In contrast, cationic lipid-mediated gene transfer has been shown to induce an inflammatory response caused by unmethylated plasmid CpG residues,... Full description

Journal Title: Gene Therapy May 2007, Vol.14(9), pp.775-80
Main Author: Zhou, R
Other Authors: Norton, J , Zhang, N , Dean, D
Format: Electronic Article Electronic Article
Language: English
Subjects:
DNA
DNA
ID: ISSN: 09697128 ; DOI: 10.1038/sj.gt.3302936
Link: http://search.proquest.com/docview/218741734/?pq-origsite=primo
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title: Electroporation-mediated transfer of plasmids to the lung results in reduced TLR9 signaling and inflammation
format: Article
creator:
  • Zhou, R
  • Norton, J
  • Zhang, N
  • Dean, D
subjects:
  • Cell Line–Administration & Dosage
  • DNA–Methods
  • Electroporation–Methods
  • Genetic Therapy–Immunology
  • Humans–Metabolism
  • Kidney–Physiology
  • Kidney–Metabolism
  • Signal Transduction–Metabolism
  • Toll-Like Receptor 9–Metabolism
  • Gene Therapy
  • Lungs
  • Deoxyribonucleic Acid
  • DNA
  • Rodents
  • Cytokines
  • Toll-Like Receptor 9
  • DNA
ispartof: Gene Therapy, May 2007, Vol.14(9), pp.775-80
description: Electroporation can deliver DNA efficiently and safely to tissues in live animals, including the lung where it causes little inflammation or lung injury. In contrast, cationic lipid-mediated gene transfer has been shown to induce an inflammatory response caused by unmethylated plasmid CpG residues, which activate the toll-like receptor (TLR9) signaling pathway. As TLR9 is located in the endosomal/lysosomal compartment, we hypothesized that plasmids do not activate TLR9 during electroporation because they enter the cytoplasm directly through transient pores in the plasma membrane. To test this, plasmids were transfected into kidney epithelial cells overexpressing TLR9 (HEK293-TLR9+) and cells lacking TLR9 (HEK293-TLR9-null). Interleukin (IL)-8 expression, an indicator of TLR9 activation, increased more than 10-fold at 24 h post-liposome transfection in HEK293-TLR9+ cells, but showed no significant increase in electroporated cells, compared with untransfected cells. In vivo liposome-mediated gene transfer caused increases in IL-6, IL-12, tumor necrosis factor alpha and interferon gamma in mouse bronchial alveolar lavage fluid, whereas the levels of these cytokines were more than 10-fold lower by comparison following electroporation. Depletion of alveolar macrophages suggested that this inflammatory response is mediated by resident pulmonary epithelial cells. These results suggest that electroporation-mediated gene transfer bypasses the TLR-9 pathway, thus accounting for the low levels of inflammation seen with this approach.
language: eng
source:
identifier: ISSN: 09697128 ; DOI: 10.1038/sj.gt.3302936
fulltext: fulltext
issn:
  • 09697128
  • 0969-7128
url: Link


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titleElectroporation-mediated transfer of plasmids to the lung results in reduced TLR9 signaling and inflammation
creatorZhou, R ; Norton, J ; Zhang, N ; Dean, D
ispartofGene Therapy, May 2007, Vol.14(9), pp.775-80
identifierISSN: 09697128 ; DOI: 10.1038/sj.gt.3302936
subjectCell Line–Administration & Dosage ; DNA–Methods ; Electroporation–Methods ; Genetic Therapy–Immunology ; Humans–Metabolism ; Kidney–Physiology ; Kidney–Metabolism ; Signal Transduction–Metabolism ; Toll-Like Receptor 9–Metabolism ; Gene Therapy ; Lungs ; Deoxyribonucleic Acid ; DNA ; Rodents ; Cytokines ; Toll-Like Receptor 9 ; DNA
descriptionElectroporation can deliver DNA efficiently and safely to tissues in live animals, including the lung where it causes little inflammation or lung injury. In contrast, cationic lipid-mediated gene transfer has been shown to induce an inflammatory response caused by unmethylated plasmid CpG residues, which activate the toll-like receptor (TLR9) signaling pathway. As TLR9 is located in the endosomal/lysosomal compartment, we hypothesized that plasmids do not activate TLR9 during electroporation because they enter the cytoplasm directly through transient pores in the plasma membrane. To test this, plasmids were transfected into kidney epithelial cells overexpressing TLR9 (HEK293-TLR9+) and cells lacking TLR9 (HEK293-TLR9-null). Interleukin (IL)-8 expression, an indicator of TLR9 activation, increased more than 10-fold at 24 h post-liposome transfection in HEK293-TLR9+ cells, but showed no significant increase in electroporated cells, compared with untransfected cells. In vivo liposome-mediated gene transfer caused increases in IL-6, IL-12, tumor necrosis factor alpha and interferon gamma in mouse bronchial alveolar lavage fluid, whereas the levels of these cytokines were more than 10-fold lower by comparison following electroporation. Depletion of alveolar macrophages suggested that this inflammatory response is mediated by resident pulmonary epithelial cells. These results suggest that electroporation-mediated gene transfer bypasses the TLR-9 pathway, thus accounting for the low levels of inflammation seen with this approach.
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titleElectroporation-mediated transfer of plasmids to the lung results in reduced TLR9 signaling and inflammation
authorZhou, R ; Norton, J ; Zhang, N ; Dean, D
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abstractElectroporation can deliver DNA efficiently and safely to tissues in live animals, including the lung where it causes little inflammation or lung injury. In contrast, cationic lipid-mediated gene transfer has been shown to induce an inflammatory response caused by unmethylated plasmid CpG residues, which activate the toll-like receptor (TLR9) signaling pathway. As TLR9 is located in the endosomal/lysosomal compartment, we hypothesized that plasmids do not activate TLR9 during electroporation because they enter the cytoplasm directly through transient pores in the plasma membrane. To test this, plasmids were transfected into kidney epithelial cells overexpressing TLR9 (HEK293-TLR9+) and cells lacking TLR9 (HEK293-TLR9-null). Interleukin (IL)-8 expression, an indicator of TLR9 activation, increased more than 10-fold at 24 h post-liposome transfection in HEK293-TLR9+ cells, but showed no significant increase in electroporated cells, compared with untransfected cells. In vivo liposome-mediated gene transfer caused increases in IL-6, IL-12, tumor necrosis factor alpha and interferon gamma in mouse bronchial alveolar lavage fluid, whereas the levels of these cytokines were more than 10-fold lower by comparison following electroporation. Depletion of alveolar macrophages suggested that this inflammatory response is mediated by resident pulmonary epithelial cells. These results suggest that electroporation-mediated gene transfer bypasses the TLR-9 pathway, thus accounting for the low levels of inflammation seen with this approach.
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pubNature Publishing Group
doi10.1038/sj.gt.3302936
urlhttp://search.proquest.com/docview/218741734/
eissn14765462
date2007-05-01