Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery
<p>Abstract</p> <p>Background</p> <p>Adenoviral vectors have provided effective methods for <it>in vivo </it>gene delivery in therapeutic applications. However, these vectors can induce immune responses that may severely affect the ability of vector re-appli...
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doaj-8f69db2da2f94da0a7fafc096dcf63f82020-11-25T03:37:15ZengBMCBMC Immunology1471-21722011-01-01121810.1186/1471-2172-12-8Evaluation of signal transduction pathways after transient cutaneous adenoviral gene deliverySteinau Hans-UlrichStupka JadwigaHirsch TobiasOtte Jan-MichelNiederbichler AndreasKesting MarcoAl-Benna SammyJacobsen FrankSorkin MichaelSteinstraesser LarsSchulte Matthias<p>Abstract</p> <p>Background</p> <p>Adenoviral vectors have provided effective methods for <it>in vivo </it>gene delivery in therapeutic applications. However, these vectors can induce immune responses that may severely affect the ability of vector re-application. There is limited information about the mechanisms and signal transduction pathways involved in adenoviral recognition. For optimization of cutaneous gene therapy it is necessary to investigate molecular mechanisms of virus recognition in epidermal cells. The aim of this study was to investigate the signal transduction of the innate immunity after adenoviral DNA internalization in keratinocytes.</p> <p>Methods</p> <p><it>In vitro</it>, keratinocytes were transfected with DNA, in the presence and absence of inhibitors for signalling molecules. <it>In vivo</it>, immunocompetent and athymic mice (n = 3 per group) were twice transduced with an Ad-vector.</p> <p>Results</p> <p>The results show an acute induction of type-I-interferon after <it>in vitro </it>transfection. Inhibition of PI3K, p38 MAPK, JNK and NFkappaB resulted in a decreased expression of type-I-interferon. In contrast to immunocompetent mice, athymic mice demonstrated a constant transgene expression and reduced inflammatory response <it>in vivo</it>.</p> <p>Conclusion</p> <p>The results suggest an induction of the innate immunity triggered by cytoplasm localised DNA which is mediated by PI3K-, p38 MAPK-, JNK-, NFkappaB-, JAK/STAT- and ERK1/2-dependent pathways. A stable transgene expression and a reduced inflammatory response in immunodeficient mice have been observed. These results provide potential for an effective adenoviral gene delivery into immunosupressed skin.</p> http://www.biomedcentral.com/1471-2172/12/8 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Steinau Hans-Ulrich Stupka Jadwiga Hirsch Tobias Otte Jan-Michel Niederbichler Andreas Kesting Marco Al-Benna Sammy Jacobsen Frank Sorkin Michael Steinstraesser Lars Schulte Matthias |
spellingShingle |
Steinau Hans-Ulrich Stupka Jadwiga Hirsch Tobias Otte Jan-Michel Niederbichler Andreas Kesting Marco Al-Benna Sammy Jacobsen Frank Sorkin Michael Steinstraesser Lars Schulte Matthias Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery BMC Immunology |
author_facet |
Steinau Hans-Ulrich Stupka Jadwiga Hirsch Tobias Otte Jan-Michel Niederbichler Andreas Kesting Marco Al-Benna Sammy Jacobsen Frank Sorkin Michael Steinstraesser Lars Schulte Matthias |
author_sort |
Steinau Hans-Ulrich |
title |
Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery |
title_short |
Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery |
title_full |
Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery |
title_fullStr |
Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery |
title_full_unstemmed |
Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery |
title_sort |
evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery |
publisher |
BMC |
series |
BMC Immunology |
issn |
1471-2172 |
publishDate |
2011-01-01 |
description |
<p>Abstract</p> <p>Background</p> <p>Adenoviral vectors have provided effective methods for <it>in vivo </it>gene delivery in therapeutic applications. However, these vectors can induce immune responses that may severely affect the ability of vector re-application. There is limited information about the mechanisms and signal transduction pathways involved in adenoviral recognition. For optimization of cutaneous gene therapy it is necessary to investigate molecular mechanisms of virus recognition in epidermal cells. The aim of this study was to investigate the signal transduction of the innate immunity after adenoviral DNA internalization in keratinocytes.</p> <p>Methods</p> <p><it>In vitro</it>, keratinocytes were transfected with DNA, in the presence and absence of inhibitors for signalling molecules. <it>In vivo</it>, immunocompetent and athymic mice (n = 3 per group) were twice transduced with an Ad-vector.</p> <p>Results</p> <p>The results show an acute induction of type-I-interferon after <it>in vitro </it>transfection. Inhibition of PI3K, p38 MAPK, JNK and NFkappaB resulted in a decreased expression of type-I-interferon. In contrast to immunocompetent mice, athymic mice demonstrated a constant transgene expression and reduced inflammatory response <it>in vivo</it>.</p> <p>Conclusion</p> <p>The results suggest an induction of the innate immunity triggered by cytoplasm localised DNA which is mediated by PI3K-, p38 MAPK-, JNK-, NFkappaB-, JAK/STAT- and ERK1/2-dependent pathways. A stable transgene expression and a reduced inflammatory response in immunodeficient mice have been observed. These results provide potential for an effective adenoviral gene delivery into immunosupressed skin.</p> |
url |
http://www.biomedcentral.com/1471-2172/12/8 |
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