Targeting cytokine expression in glial cells by cellular delivery of an NF-kappaB decoy.
Inhibition of nuclear factor (NF)-kappaB has emerged as an important strategy for design of anti-inflammatory therapies. In neurodegenerative disorders like Alzheimer's disease, inflammatory reactions mediated by glial cells are believed to promote disease progression. Here, we report that uptake of a double-stranded oligonucleotide NF-kappaB decoy in rat primary glial cells is clearly facilitated by noncovalent binding to a cell-penetrating peptide, transportan 10, via a complementary peptide nucleic acid (PNA) sequence. Fluorescently labeled oligonucleotide decoy was detected in the cells within 1 h only when cells were incubated with the decoy in the presence of cell-penetrating peptide. Cellular delivery of the decoy also inhibited effects induced by a neurotoxic fragment of the Alzheimer beta-amyloid peptide in the presence of the inflammatory cytokine interleukin (IL)-1beta. Pretreatment of the cells with the complex formed by the decoy and the cell-penetrating peptide-PNA resulted in 80% and 50% inhibition of the NF-kappaB binding activity and IL-6 mRNA expression, respectively.
Fisher
Linda
L
Department of Neurochemistry, Stockholm University, SE10691 Stockholm, Sweden.
Samuelsson
Malin
M
Jiang
Yang
Y
Ramberg
Veronica
V
Figueroa
Ricardo
R
Hallberg
Einar
E
Langel
Ulo
U
Iverfeldt
Kerstin
K
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D010455:Peptides