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Adenovirus binding to cultured synoviocytes triggers signaling through MAPK pathways and induces expression of cyclooxygenase‐2
Author(s) -
Crofford Leslie J.,
McDonagh Kevin T.,
Guo Sutang,
Mehta Hemal,
Bian Huimin,
Petruzelli Lilli M.,
Roessler Blake J.
Publication year - 2005
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.661
Subject(s) - mapk/erk pathway , signal transduction , microbiology and biotechnology , p38 mitogen activated protein kinases , adenoviridae , biology , chemistry , genetic enhancement , gene , biochemistry
Background Recombinant adenovirus can be administered in vivo to achieve transduction of a number of cell types including human synoviocytes. Immunogenicity of adenoviruses has limited their utility as vectors for gene delivery; however, specific mechanisms underlying the acute inflammatory response to adenovirus are not well understood. Activation of a number of signal transduction pathways occurs rapidly upon adenovirus binding to cell‐surface receptors. We investigated stimulated expression of mitogen‐activated protein kinases (MAPKs), cyclooxygenase‐2 (COX‐2) and prostaglandin E 2 (PGE 2 ) in human primary synovial fibroblasts to adenovirus expressing the E. coli β‐galactosidase gene. Methods Cultured rheumatoid synoviocytes were exposed to transduction‐competent Ad/RSVlacZ recombinant adenovirus or transduction‐incompetent (psoralen/UV‐irradiated) Ad/RSVlacZ. The effects on COX‐2 expression, PGE 2 levels and MAPK signaling in synoviocytes were assessed using a combination of reverse‐transcription polymerase chain reaction amplification and immunoblotting. Results Adenovirus treatment of synoviocytes increased levels of COX‐2 mRNA and protein as well as PGE 2 . Psoralen‐treated transcriptionally inactive adenovirus was equivalent to untreated adenovirus for early COX‐2 induction suggesting that viral genes were not required. Adenovirus treatment stimulated phosphorylation of ERK‐1/‐2, p38 MAPK, and JNK. Inhibition of the ERK and p38 MAPK pathways inhibited COX‐2 expression and PGE 2 production. Conclusions Taken together, these data demonstrate that a MAPK‐dependent increase in COX‐2 results in local prostaglandin production. These findings have clinical implications for use of adenovirus as vectors for in vivo gene delivery. Copyright © 2004 John Wiley & Sons, Ltd.