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Journal of Virology, August 2002, p. 8236-8243, Vol. 76, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.16.8236-8243.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inhibition of Chemokine Expression by Adenovirus Early Region Three (E3) Genes

Alexander M. Lesokhin, Fernando Delgado-Lopez, and Marshall S. Horwitz*

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

Received 14 March 2002/ Accepted 12 May 2002

Adenoviruses (Ad) have a variety of immunoregulatory genes, many of which are clustered in a 3.5-kb segment of DNA known as early region 3 (E3). Ad E3 codes for proteins that downregulate surface expression of class I major histocompatibility antigens and also inhibit tumor necrosis factor alpha (TNF-{alpha})- and Fas-induced cytolysis. We were interested in determining whether chemokine production or activity might also be inhibited by Ad E3 and we have studied this function in a human astrocytoma cell line, U373. Astrocytes constitute a part of the blood-brain barrier, and chemokines (IP-10, IL-8, MCP-1-4, and MIPs) expressed by them may contribute to leukocyte infiltration within the brain during inflammation. When U373 cells are activated by the proinflammatory molecule TNF-{alpha}, the increase in chemokine MCP-1, IL-8, and IP-10 transcripts is blocked by a recombinant Ad expressing the E3 genes under cytomegalovirus promoter control. Comparable Ads expressing green fluorescent protein in place of E3 have no effect on these chemokines. Ads also have been extensively studied as gene therapy vectors and most have a deletion of the E3 region to permit the insertion of larger fragments of foreign DNA. Our results suggest that construction of Ad vectors to include E3 expression cassettes will improve the efficacy and safety of such viral-based gene therapy protocols.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Room 411 Forchheimer Building, Bronx, NY 10461. Phone: (718) 430-2230. Fax: (718) 430-8702. E-mail: horwitz{at}aecom.yu.edu.

Journal of Virology, August 2002, p. 8236-8243, Vol. 76, No. 16
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.16.8236-8243.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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