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Journal of Virology, July 2001, p. 6428-6439, Vol. 75, No. 14
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.14.6428-6439.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Multiple cis Regulatory Elements Control RANTES Promoter Activity in Alveolar Epithelial Cells Infected with Respiratory Syncytial Virus

Antonella Casola,1,* Roberto P. Garofalo,1,2 Helene Haeberle,1 Todd F. Elliott,1 Rongtuan Lin,3 Mohammad Jamaluddin,4 and Allan R. Brasier4,5

Departments of Pediatrics,1 Microbiology and Immunology,2 and Internal Medicine4 and Sealy Center for Molecular Sciences,5 University of Texas Medical Branch, Galveston, Texas, and Lady Davis Institute for Medical Research and Department of Medicine, McGill University, Montreal, Quebec, Canada3

Received 16 January 2001/Accepted 19 April 2001

Respiratory syncytial virus (RSV) produces intense pulmonary inflammation, in part through its ability to induce chemokine synthesis in infected airway epithelial cells. RANTES (regulated upon activation, normally T-cell expressed and presumably secreted) is a CC chemokine which recruits and activates monocytes, lymphocytes, and eosinophils, all cell types present in the lung inflammatory infiltrate induced by RSV infection. In this study, we analyzed the mechanism of RSV-induced RANTES promoter activation in human type II alveolar epithelial cells (A549 cells). Promoter deletion and mutagenesis experiments indicate that RSV requires the presence of five different cis regulatory elements, located in the promoter fragment spanning from -220 to +55 nucleotides, corresponding to NF-kappa B, C/EBP, Jun/CREB/ATF, and interferon regulatory factor (IRF) binding sites. Although site mutations of the NF-kappa B, C/EBP, and CREB/AP-1 like sites reduce RSV-induced RANTES gene transcription to 50% or less, only mutations affecting IRF binding completely abolish RANTES inducibility. Supershift and microaffinity isolation assays were used to identify the different transcription factor family members whose DNA binding activity was RSV inducible. Expression of dominant negative mutants of these transcription factors further established their central role in virus-induced RANTES promoter activation. Our finding that the presence of multiple cis regulatory elements is required for full activation of the RANTES promoter in RSV-infected alveolar epithelial cells supports the enhanceosome model for RANTES gene transcription, which is absolutely dependent on binding of IRF transcription factors. The identification of regulatory mechanisms of RANTES gene expression is fundamental for rational design of inhibitors of RSV-induced lung inflammation.

* Corresponding author. Mailing address: Department of Pediatrics, Division of Child Health Research Center, 301 University Blvd., Galveston, TX 77555-0366. Phone: (409) 747-0581. Fax: (409) 772-1761. E-mail: ancasola{at}utmb.edu.

Journal of Virology, July 2001, p. 6428-6439, Vol. 75, No. 14
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.14.6428-6439.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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