In vivo transfection of a cis element 'decoy' against signal transducers and activators of transcription 6 (STAT6)-binding site ameliorates IgE-mediated late-phase reaction in an atopic dermatitis mouse model.
Signal transducers and activators of transcription 6 (STAT6) play a crucial role in the transactivation of IL-4 and IL-13, which might be involved in the pathogenesis of atopic dermatitis (AD). We herein reported that the IgE-mediated late-phase reaction significantly decreased in STAT6-deficient (STAT6(-/-)) mice in AD model mice induced by intravenous injection of monoclonal anti-dinitrophenyl (DNP)-IgE antibody and subsequent skin testing with dinitrofluorobenzene. We therefore hypothesized that synthetic double-stranded DNA with a high affinity for STAT6 could be introduced in vivo as decoy cis elements to bind the transcriptional factor and block the gene activation contributing to the onset and progression of AD, thus providing effective therapy for AD. Treatment by the transfection of STAT6 decoy oligodeoxynucleotides (ODNs), but not scramble decoy ODN after sensitization by anti-DNP-IgE antibody, had a significant inhibitory effect on not only STAT6 binding to nuclei but also on the late-phase response. A histological analysis revealed that both edema and the infiltration of neutrophils and eosinophils significantly decreased in STAT6 decoy ODN-transfected mice. To examine the mechanism of the in vivo effect of STAT6 decoy ODN, we employed an in vitro mast cells culture system. After IgE receptor engagement, mast cells transfected by STAT6 decoy ODN exhibited normal histamine release, but their cytokine release (TNF-alpha, IL-6) markedly decreased. We herein report the first successful in vivo transfer of STAT6 decoy ODN to reduce the late-phase reaction, thereby providing a new therapeutic strategy for AD.
Department of Dermatology and Immunodermatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
H
H
Yokozeki
M-H
MH
Wu
K
K
Sumi
S
S
Awad
T
T
Satoh
I
I
Katayama
K
K
Takeda
S
S
Akira
Y
Y
Kaneda
K
K
Nishioka
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004140:Dinitrophenols / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007073:Immunoglobulin E / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D004140:Dinitrophenols; D009838:Oligodeoxyribonucleotides; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D007073:Immunoglobulin E