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Journal of Virology, July 2001, p. 6450-6459, Vol. 75, No. 14
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.14.6450-6459.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Adenovirus Type 7 Induces Interleukin-8 Production via Activation of Extracellular Regulated Kinase 1/2

M. J. Alcorn,1,2 J. L. Booth,3 K. M. Coggeshall,1,2 and J. P. Metcalf1,3,*

Pulmonary and Critical Care Division of the Department of Medicine3 and Department of Microbiology and Immunology,1 University of Oklahoma Health Sciences Center, and Program in Immunobiology and Cancer, Oklahoma Medical Research Foundation,2 Oklahoma City, Oklahoma

Received 16 January 2001/Accepted 13 April 2001

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.

* Corresponding author. Mailing address: OU Health Sciences Center, 800 N. Research Pkwy., Oklahoma City, OK 73104. Phone: (405) 271-6173. Fax: (405) 271-5440. E-mail: jordan-metcalf{at}ouhsc.edu.

Journal of Virology, July 2001, p. 6450-6459, Vol. 75, No. 14
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.14.6450-6459.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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