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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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