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Cellular delivery of a double-stranded oligonucleotide NFκB decoy by hybridization to complementary PNA linked to a cell-penetrating peptide
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology. University of Tartu, Estonia.
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
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2004 (English)In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 11, 1264-1272 p.Article in journal (Refereed) Published
Abstract [en]

The activation of nuclear factor B (NFB) is a key event in immune and inflammatory responses. In this study, a cell-penetrating transport peptide, transportan (TP) or its shorter analogue TP 10, was used to facilitate the cellular uptake of an NFB decoy. Peptide nucleic acid (PNA) hexamer or nonamer was linked to the transport peptide by a disulfide bond. NFB decoy oligonucleotide consisted of a double-stranded consensus sequence corresponding to the B site localized in the IL-6 gene promoter, 5'-GGGACTTTCCC-3', with a single-stranded protruding 3'-terminal sequence complementary to the PNA sequence was hybridized to the transport peptide–PNA construct. The ability of the transport peptide–PNA–NFB decoy complex to block the effect of interleukin (IL)-1-induced NFB activation and IL-6 gene expression was analyzed by electrophoretic mobility shift assay and reverse transcriptase-polymerase chain reaction in rat Rinm5F insulinoma cells. Preincubation with transport peptide–PNA–NFB decoy (1 M, 1 h) blocked IL-1-induced NFB-binding activity and significantly reduced the IL-6 mRNA expression. The same concentration of NFB decoy in the absence of transport peptide–PNA had no effect even after longer incubations. Our results showed that binding of the oligonucleotide NFB decoy to the nonamer PNA sequence resulted in a stable complex that was efficiently translocated across the plasma membrane.

Place, publisher, year, edition, pages
2004. Vol. 11, 1264-1272 p.
Keyword [en]
nuclear factor decoy, NFkappaB, PNA, transport peptide, interleukin-1beta, interleukin-6
National Category
Biological Sciences Chemical Sciences
URN: urn:nbn:se:su:diva-25919DOI: 10.1038/ diva2:200800
Available from: 2006-05-18 Created: 2006-05-18 Last updated: 2015-09-04Bibliographically approved
In thesis
1. Inflammatory cytokines and NFκB in Alzheimer’s disease
Open this publication in new window or tab >>Inflammatory cytokines and NFκB in Alzheimer’s disease
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease is the most common form of dementia. It is a neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles. The main constituent of the senile plaques is the neurotoxic β-amyloid peptide. Surrounding the senile plaques are activated astrocytes and microglia, believed to contribute to neurotoxicity through secretion of proinflammatory cytokines, like interleukin-1β and interleukin-6. For many inflammatory actions, including the cytokine induction in glial cells, the transcription factor NFκB plays a key role. This suggests that therapeutical strategies aimed to control the development of Alzheimer’s disease could include administration of drugs that hinder NFκB activation.

The major aim of this thesis was to examine the effects of β-amyloid together with interleukin-1β on cytokine expression as well as NFκB activation in glial cells. The possibility to block NFκB activation, and downstream effects like interleukin-6 expression, by using an NFκB decoy was investigated. The possibility to improve the cellular uptake of the decoy by linking it to a cell-penetrating peptide was also investigated.

The results obtained provide supportive evidence that inflammatory cytokines are induced by β-amyloid, and that they can indeed potentiate its effects. The results further demonstrate that by blocking NFκB activation, the induction of interleukin-6 expression can be inhibited. By using an improved cellular delivery system, the uptake of the NFκB decoy and hence the downstream cytokine inhibition could be increased. In conclusion, these results demonstrate the possibility to decrease the inflammatory reactions taken place in Alzheimer’s disease brains, which may ultimately lead to a possible way of controlling this disorder.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi, 2006. 130 p.
β-amyloid, interleukin-1, interleukin-6, cell-penetrating peptide, PNA
National Category
urn:nbn:se:su:diva-990 (URN)91-7155-265-0 (ISBN)
Public defence
2006-06-09, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00
Available from: 2006-05-18 Created: 2006-05-18Bibliographically approved

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Langel, UloIverfeldt, Kerstin
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