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

被引:12
作者
Crofford, LJ
McDonagh, KT
Guo, ST
Mehta, H
Bian, HM
Petruzelli, LM
Roessler, BJ
机构
[1] Univ Michigan, Dept Internal Med, Div Rheumatol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Internal Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA
关键词
adenovirus; cyclooxygenase-2; synoviocytes; MAPK;
D O I
10.1002/jgm.661
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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 beta-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 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 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 (c) 2004 John Wiley & Sons, Ltd.
引用
收藏
页码:288 / 296
页数:9
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