High adenoviral loads stimulate NFκB-dependent gene expression in human vascular smooth muscle cells

Clesham, GJ; Adam, PJ; Proudfoot, Diane; Flynn, Paul D; Efstathiou, Stacey; Weissberg, PL

doi:10.1038/sj.gt.3300576

Cited by 65 publications

(47 citation statements)

References 12 publications

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“…The number of GFP-positive cells in the scAAV infected cultures was increased by only 1.6-fold, an effect which could be attributed to the transcriptional effects of adenovirus infection on the activity of the CMV promoter as previously reported. 27,28 The monomer vector transduction rate was increased 2.4-fold by Ad coinfection, while the GFPneo and LacZ vectors were induced 6.0-fold and 12.8-fold, respectively.…”

Section: Transduction With Dimeric Versus Monomeric Raav Vectors and mentioning

confidence: 99%

Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis

2001

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Section: Transduction With Dimeric Versus Monomeric Raav Vectors and mentioning

confidence: 99%

Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis

2001

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“…It has been reported that activated Kupffer cells (and monocytes and resident macrophages) and dendritic cells (DC) release proinflammatory cytokines/chemokines such as IL-6, TNF-␣, IP-10, and RANTES, causing the activation of an innate immune response (14,15). NF-B activation is likely to play a central role in inflammatory cytokine/chemokine production (16,17). Although many papers regarding the innate immune response to the Ad vector have been published thus far, the biological mechanism has not been clearly elucidated.…”

Section: Fiber-modified Adenovirus Vectors Decrease Livermentioning

confidence: 99%

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

Koizumi

Yamaguchi

Kono

et al. 2007

The Journal of Immunology

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Adenovirus (Ad) vectors are one of the most commonly used viral vectors in gene therapy clinical trials. However, they elicit a robust innate immune response and inflammatory responses. Improvement of the therapeutic index of Ad vector gene therapy requires elucidation of the mechanism of Ad vector-induced inflammation and cytokine/chemokine production as well as development of the safer vector. In the present study, we found that the fiber-modified Ad vector containing poly-lysine peptides in the fiber knob showed much lower serum IL-6 and aspartate aminotransferase levels (as a maker of liver toxicity) than the conventional Ad vector after i.v. administration, although the modified Ad vector showed higher transgene production in the liver than the conventional Ad vector. RT-PCR analysis showed that spleen, not liver, is the major site of cytokine, chemokine, and IFN expression. Splenic CD11c+ cells were found to secret cytokines. The tissue distribution of Ad vector DNA showed that spleen distribution was much reduced in this modified Ad vector, reflecting reduced IL-6 levels in serum. Liver toxicity by the conventional Ad vector was reduced by anti-IL-6R Ab, suggesting that IL-6 signaling is involved in liver toxicity and that decreased liver toxicity of the modified Ad vector was due in part to the reduced IL-6 production. This study contributes to an understanding of the biological mechanism in innate immune host responses and liver toxicity toward systemically administered Ad vectors and will help in designing safer gene therapy methods that can reduce robust innate immunity and inflammatory responses.

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“…[5][6][7] Recombinant adenoviral vectors have been shown to activate NF-kB in murine hepatocytes, murine dendritic cells and human vascular smooth muscle cells. [8][9][10] These reports suggested a role for NFkB in the transcriptional regulation of ICAM-1 gene induced by Ad.CFTR. Inactive NF-kB/Rel proteins are located in the cytoplasm as heterodimers and homodimers which are bound to inhibitory proteins termed IkBs.…”

Section: Moter Adcftr Also Stimulated a 13-fold Increase In Nfkb-dementioning

confidence: 99%

Activation of NF-kB mediates ICAM-1 induction in respiratory cells exposed to an adenovirus-derived vector

et al. 2001

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Gene transfer to the respiratory tract by replication-deficient adenoviruses is limited by the induction of inflammatory and immune responses. We previously demonstrated that a E1-E3-deleted recombinant adenovirus carrying the expression cassette for the cystic fibrosis gene (Ad.CFTR) upregulates the expression of the pro-inflammatory intercellular adhesion molecule-1 (ICAM-1) both in vitro and in vivo. In the present work we suggest a role for the nuclear factor-kB (NF-kB) in Ad.CFTR-dependent up-regulation of ICAM-1 in respiratory epithelial A549 cells. Specifically, Ad.CFTR induced translocation of NF-kB into the nucleus and binding to the proximal −228/−218 NF-kB consensus sequence on the ICAM-1 pro-

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High adenoviral loads stimulate NFκB-dependent gene expression in human vascular smooth muscle cells

Cited by 65 publications

References 12 publications

Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis

Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis

Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production

Activation of NF-kB mediates ICAM-1 induction in respiratory cells exposed to an adenovirus-derived vector

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