Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery

BMC Immunology

Research Article

Jan-Michel Otte¹  Marco Rainer Kesting²  Andreas David Niederbichler³  Tobias Hirsch⁴  Frank Jacobsen⁴  Hans-Ulrich Steinau⁴  Matthias Schulte⁴  Jadwiga Stupka⁴  Michael Sorkin⁴  Lars Steinstraesser⁴  Sammy Al-Benna⁴ 

[1] Dept. of Gastroenterology, St. Josef - Hospital, Ruhr University Bochum, Bochum, Germany;Dept. of Oral and Maxillofacial Surgery, Klinikum Rechts der Isar der Technischen Universität München, München, Germany;Dept. of Plastic, Hand and Reconstructive Surgery, Burn Center, Medizinische Hochschule Hannover, Hannorver, Germany;Laboratory for Molecular Oncology and Wound Healing, Department of Plastic Surgery, Operative Reference Centre for Soft Tissue Sarcomas, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany;

关键词: Adenoviral Vector;    HaCaT Cell;    Green Fluorescent Protein Expression;    Relative Light Unit;    Immunocompetent Mouse;   

DOI  :  10.1186/1471-2172-12-8

 received in 2010-06-09, accepted in 2011-01-21,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundAdenoviral vectors have provided effective methods for in vivo 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.MethodsIn vitro, keratinocytes were transfected with DNA, in the presence and absence of inhibitors for signalling molecules. In vivo, immunocompetent and athymic mice (n = 3 per group) were twice transduced with an Ad-vector.ResultsThe results show an acute induction of type-I-interferon after in vitro 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 in vivo.ConclusionThe 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.

【 授权许可】

Unknown   
© Lars et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.