Adenovirus binding to cultured synoviocytes triggers signaling through MAPK pathways and induces expression of cyclooxygenase-2

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 E2 (PGE2) 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, PGE2 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 PGE2. 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 PGE2 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.