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

Ken Ichi Ogawara, Joanna M. Kułdo, Koen Oosterhuis, Bart Jan Kroesen, Marianne G. Rots, Christian Trautwein, Toshikiro Kimura, Hidde J. Haisma, Grietje Molema

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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 coxsackiadenovirus 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, VEGFA 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.

Original languageEnglish
Article numberR32
JournalArthritis Research and Therapy
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 13 2006

Fingerprint

Intercellular Adhesion Molecule-1
Adenoviridae
Integrins
Signal Transduction
E-Selectin
Endothelial Cells
Vascular Cell Adhesion Molecule-1
Interleukin-8
Interleukin-6
Tumor Necrosis Factor-alpha
TYK2 Kinase
Genes
Vascular Endothelial Growth Factor Receptor
Cell Adhesion Molecules
Transgenes
Inflammatory Bowel Diseases
Vascular Endothelial Growth Factor A
Reverse Transcription
Endothelium
Rheumatoid Arthritis

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

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.

In: Arthritis Research and Therapy, Vol. 8, No. 1, R32, 13.01.2006.

Research output: Contribution to journalArticle

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. In: Arthritis Research and Therapy. 2006 ; Vol. 8, No. 1.
@article{671f3a2e4e52496bafb375bcb41d0d2a,
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",
abstract = "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 coxsackiadenovirus 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, VEGFA 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.",
author = "Ogawara, {Ken Ichi} and Kułdo, {Joanna M.} and Koen Oosterhuis and Kroesen, {Bart Jan} and Rots, {Marianne G.} and Christian Trautwein and Toshikiro Kimura and Haisma, {Hidde J.} and Grietje Molema",
year = "2006",
month = "1",
day = "13",
doi = "10.1186/ar1885",
language = "English",
volume = "8",
journal = "Arthritis Research and Therapy",
issn = "1478-6354",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Functional inhibition of NF-κB signal transduction in αvβ3 integrin expressing endothelial cells by using RGD-PEG-modified adenovirus with a mutant IκB gene

AU - Ogawara, Ken Ichi

AU - Kułdo, Joanna M.

AU - Oosterhuis, Koen

AU - Kroesen, Bart Jan

AU - Rots, Marianne G.

AU - Trautwein, Christian

AU - Kimura, Toshikiro

AU - Haisma, Hidde J.

AU - Molema, Grietje

PY - 2006/1/13

Y1 - 2006/1/13

N2 - 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 coxsackiadenovirus 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, VEGFA 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.

AB - 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 coxsackiadenovirus 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, VEGFA 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.

UR - http://www.scopus.com/inward/record.url?scp=70350501443&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350501443&partnerID=8YFLogxK

U2 - 10.1186/ar1885

DO - 10.1186/ar1885

M3 - Article

C2 - 16803639

AN - SCOPUS:70350501443

VL - 8

JO - Arthritis Research and Therapy

JF - Arthritis Research and Therapy

SN - 1478-6354

IS - 1

M1 - R32

ER -