Adenovirus type 7 induces interleukin-8 production via activation of extracellular regulated kinase 1/2.
Infection with adenovirus serotype 7 (Ad7) frequently causes lower respiratory pneumonia and is associated with severe lung inflammation and neutrophil infiltration. Earlier studies indicated release of proinflammatory cytokines, specifically interleukin-8 (IL-8), by pulmonary epithelial cells following infection by Ad7. However, the mechanism of IL-8 induction by Ad7 is unclear. We have explored the role of the Ras/Raf/MEK/Erk pathway in the Ad7-associated induction of IL-8 using a model system of A549 epithelial cells. We found that Ad7 infection induced a rapid activation of epithelial cell-derived Erk. The MEK-specific inhibitors PD98059 and U0126 blocked Erk activation and release of IL-8 following infection with Ad7. Treatment with PD98059 is cytostatic and not cytotoxic, as treated cells regain the ability to phosphorylate Erk and secrete IL-8 after removal of the drug. The expression of a mutated form of Ras in A549 epithelial cells blocked the induction of IL-8 promoter activity, and MEK inhibitor blocked induction of IL-8 mRNA. These results suggest that the Ras/Raf/MEK/Erk pathway is necessary for the Ad7 induction of IL-8 and that induction occurs at the level of transcription. Further, the kinetics of Erk activation and IL-8 induction suggest that an early viral event, such as receptor binding, may be responsible for the observed inflammatory response.
Alcorn
M J
MJ
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, 800 N. Research Pkwy., Oklahoma City, OK 73104, USA.
Booth
J L
JL
Coggeshall
K M
KM
Metcalf
J P
JP
D000256:Adenoviridae / Q000276:immunology*; D000257:Adenoviridae Infections / Q000628:therapy; D002070:Butadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D015316:Genetic Therapy; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016209:Interleukin-8; D009570:Nitriles; D012333:RNA, Messenger; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one