Cargando…

Functional inhibition of NF-κB signal transduction in αvβ3 integrin expressing endothelial cells by using RGD-PEG-modified adenovirus with a mutant IκB gene

In order to selectively block nuclear factor κB (NF-κB)-dependent signal transduction in angiogenic endothelial cells, we constructed an αvβ3 integrin specific adenovirus encoding dominant negative IκB (dnIκB) as a therapeutic gene. By virtue of RGD modification of the PEGylated virus, the specifici...

Descripción completa

Detalles Bibliográficos
Autores principales: Ogawara, Ken-ichi, Kułdo, Joanna M, Oosterhuis, Koen, Kroesen, Bart-Jan, Rots, Marianne G, Trautwein, Christian, Kimura, Toshikiro, Haisma, Hidde J, Molema, Grietje
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1526577/
https://www.ncbi.nlm.nih.gov/pubmed/16803639
http://dx.doi.org/10.1186/ar1885
_version_ 1782128915676921856
author Ogawara, Ken-ichi
Kułdo, Joanna M
Oosterhuis, Koen
Kroesen, Bart-Jan
Rots, Marianne G
Trautwein, Christian
Kimura, Toshikiro
Haisma, Hidde J
Molema, Grietje
author_facet Ogawara, Ken-ichi
Kułdo, Joanna M
Oosterhuis, Koen
Kroesen, Bart-Jan
Rots, Marianne G
Trautwein, Christian
Kimura, Toshikiro
Haisma, Hidde J
Molema, Grietje
author_sort Ogawara, Ken-ichi
collection PubMed
description In order to selectively block nuclear factor κB (NF-κB)-dependent signal transduction in angiogenic endothelial cells, we constructed an αvβ3 integrin specific adenovirus encoding dominant negative IκB (dnIκB) as a therapeutic gene. By virtue of RGD modification of the PEGylated virus, the specificity of the cell entry pathway of adenovirus shifted from coxsacki-adenovirus receptor dependent to αvβ3 integrin dependent entry. The therapeutic outcome of delivery of the transgene into endothelial cells was determined by analysis of cellular responsiveness to tumor necrosis factor (TNF)-α. Using real time reverse transcription PCR, mRNA levels of the cell adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, the cytokines/growth factors IL-6, IL-8 and vascular endothelial growth factor (VEGF)-A, and the receptor tyrosine kinase Tie-2 were assessed. Furthermore, levels of ICAM-1 protein were determined by flow cytometric analysis. RGD-targeted adenovirus delivered the dnIκB via αvβ3 to become functionally expressed, leading to complete abolishment of TNF-α-induced up-regulation of E-selectin, ICAM-1, VCAM-1, IL-6, IL-8, VEGF-A and Tie-2. The approach of targeted delivery of dnIκB into endothelial cells presented here can be employed for diseases such as rheumatoid arthritis and inflammatory bowel disease where activation of NF-κB activity should be locally restored to basal levels in the endothelium.
format Text
id pubmed-1526577
institution National Center for Biotechnology Information
language English
publishDate 2006
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-15265772006-08-04 Functional inhibition of NF-κB signal transduction in αvβ3 integrin expressing endothelial cells by using RGD-PEG-modified adenovirus with a mutant IκB gene Ogawara, Ken-ichi Kułdo, Joanna M Oosterhuis, Koen Kroesen, Bart-Jan Rots, Marianne G Trautwein, Christian Kimura, Toshikiro Haisma, Hidde J Molema, Grietje Arthritis Res Ther Research Article In order to selectively block nuclear factor κB (NF-κB)-dependent signal transduction in angiogenic endothelial cells, we constructed an αvβ3 integrin specific adenovirus encoding dominant negative IκB (dnIκB) as a therapeutic gene. By virtue of RGD modification of the PEGylated virus, the specificity of the cell entry pathway of adenovirus shifted from coxsacki-adenovirus receptor dependent to αvβ3 integrin dependent entry. The therapeutic outcome of delivery of the transgene into endothelial cells was determined by analysis of cellular responsiveness to tumor necrosis factor (TNF)-α. Using real time reverse transcription PCR, mRNA levels of the cell adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, the cytokines/growth factors IL-6, IL-8 and vascular endothelial growth factor (VEGF)-A, and the receptor tyrosine kinase Tie-2 were assessed. Furthermore, levels of ICAM-1 protein were determined by flow cytometric analysis. RGD-targeted adenovirus delivered the dnIκB via αvβ3 to become functionally expressed, leading to complete abolishment of TNF-α-induced up-regulation of E-selectin, ICAM-1, VCAM-1, IL-6, IL-8, VEGF-A and Tie-2. The approach of targeted delivery of dnIκB into endothelial cells presented here can be employed for diseases such as rheumatoid arthritis and inflammatory bowel disease where activation of NF-κB activity should be locally restored to basal levels in the endothelium. BioMed Central 2006 2006-01-13 /pmc/articles/PMC1526577/ /pubmed/16803639 http://dx.doi.org/10.1186/ar1885 Text en Copyright © 2006 Ogawara et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Ogawara, Ken-ichi
Kułdo, Joanna M
Oosterhuis, Koen
Kroesen, Bart-Jan
Rots, Marianne G
Trautwein, Christian
Kimura, Toshikiro
Haisma, Hidde J
Molema, Grietje
Functional inhibition of NF-κB signal transduction in αvβ3 integrin expressing endothelial cells by using RGD-PEG-modified adenovirus with a mutant IκB gene
title Functional inhibition of NF-κB signal transduction in αvβ3 integrin expressing endothelial cells by using RGD-PEG-modified adenovirus with a mutant IκB gene
title_full Functional inhibition of NF-κB signal transduction in αvβ3 integrin expressing endothelial cells by using RGD-PEG-modified adenovirus with a mutant IκB gene
title_fullStr Functional inhibition of NF-κB signal transduction in αvβ3 integrin expressing endothelial cells by using RGD-PEG-modified adenovirus with a mutant IκB gene
title_full_unstemmed Functional inhibition of NF-κB signal transduction in αvβ3 integrin expressing endothelial cells by using RGD-PEG-modified adenovirus with a mutant IκB gene
title_short Functional inhibition of NF-κB signal transduction in αvβ3 integrin expressing endothelial cells by using RGD-PEG-modified adenovirus with a mutant IκB gene
title_sort functional inhibition of nf-κb signal transduction in αvβ3 integrin expressing endothelial cells by using rgd-peg-modified adenovirus with a mutant iκb gene
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1526577/
https://www.ncbi.nlm.nih.gov/pubmed/16803639
http://dx.doi.org/10.1186/ar1885
work_keys_str_mv AT ogawarakenichi functionalinhibitionofnfkbsignaltransductioninavb3integrinexpressingendothelialcellsbyusingrgdpegmodifiedadenoviruswithamutantikbgene
AT kułdojoannam functionalinhibitionofnfkbsignaltransductioninavb3integrinexpressingendothelialcellsbyusingrgdpegmodifiedadenoviruswithamutantikbgene
AT oosterhuiskoen functionalinhibitionofnfkbsignaltransductioninavb3integrinexpressingendothelialcellsbyusingrgdpegmodifiedadenoviruswithamutantikbgene
AT kroesenbartjan functionalinhibitionofnfkbsignaltransductioninavb3integrinexpressingendothelialcellsbyusingrgdpegmodifiedadenoviruswithamutantikbgene
AT rotsmarianneg functionalinhibitionofnfkbsignaltransductioninavb3integrinexpressingendothelialcellsbyusingrgdpegmodifiedadenoviruswithamutantikbgene
AT trautweinchristian functionalinhibitionofnfkbsignaltransductioninavb3integrinexpressingendothelialcellsbyusingrgdpegmodifiedadenoviruswithamutantikbgene
AT kimuratoshikiro functionalinhibitionofnfkbsignaltransductioninavb3integrinexpressingendothelialcellsbyusingrgdpegmodifiedadenoviruswithamutantikbgene
AT haismahiddej functionalinhibitionofnfkbsignaltransductioninavb3integrinexpressingendothelialcellsbyusingrgdpegmodifiedadenoviruswithamutantikbgene
AT molemagrietje functionalinhibitionofnfkbsignaltransductioninavb3integrinexpressingendothelialcellsbyusingrgdpegmodifiedadenoviruswithamutantikbgene