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- Title
Activation of NF-kB mediates ICAM-1 induction in respiratory cells exposed to an adenovirus-derived vector.
- Authors
Melotti, P; Nicolis, E; Tamanini, A; Rolfini, R; Pavirani, A; Cabrini, G
- Abstract
Gene transfer to the respiratory tract by replication-deficient adenoviruses is limited by the induction of inflammatory and immune responses. We previously demonstrated that a E1E3-deleted recombinant adenovirus carrying the expression cassette for the cystic fibrosis gene (Ad.CFTR) upregulates the expression of the pro-inflammatory intercellular adhesion molecule-1 (ICAM-1) both in vitro and in vivo. In the present work we suggest a role for the nuclear factor-kB (NF-kB) in Ad. CFTR-dependent up-regulation of ICAM-1 in respiratory epithelial A549 cells. Specifically, Ad.CFTR induced translocation of NF-kB into the nucleus and binding to the proximal -228/-218 NF-kB consensus sequence on the ICAM-1 pro- moter. Ad.CFTR also stimulated a 13-fold increase in NFkB-dependent expression of the CAT reporter gene under the control of a region of the ICAM-1 promoter, including the proximal NF-kB consensus sequence. The Ad.CFTR-dependent increase of ICAM-1 mRNA was abolished by inhibitors of NF-kB, such as N-acetyl-L-cysteine, pyrrolidine dithiocarbamate, parthenolide and the synthetic peptide SN50. All these inhibitors abolished both Ad.CFTR-induced NF-kB DNA binding and transactivating activities. These results indicate a critical role of NF-kB in the pro-inflammatory response elicited by replication-deficient adenoviral vectors in respiratory cells.
- Subjects
CELL adhesion molecules; CYSTIC fibrosis; GENE therapy; ADENOVIRUSES
- Publication
Gene Therapy, 2001, Vol 8, Issue 18, p1436
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3301533