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Journal of Virology, October 2000, p. 9617-9628, Vol. 74, No. 20
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Recombinant Adenovirus Induces Maturation of Dendritic Cells via an NF-kappa B-Dependent Pathway

Adrian E. Morelli,1,2,* Adriana T. Larregina,3 Raymond W. Ganster,2 Alan F. Zahorchak,1,2 Jeffrey M. Plowey,3 Takuya Takayama,1,2 Alison J. Logar,1,2 Paul D. Robbins,4 Louis D. Falo,3 and Angus W. Thomson1,2,4

Thomas E. Starzl Transplantation Institute,1 Department of Surgery,2 Department of Molecular Genetics and Biochemistry,4 and Department of Dermatology and the University of Pittsburgh Cancer Institute,3 University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213-2582

Received 5 May 2000/Accepted 12 July 2000

Recombinant adenovirus (rAd) infection is one of the most effective and frequently employed methods to transduce dendritic cells (DC). Contradictory results have been reported recently concerning the influence of rAd on the differentiation and activation of DC. In this report, we show that, as a result of rAd infection, mouse bone marrow-derived immature DC upregulate expression of major histocompatibility complex class I and II antigens, costimulatory molecules (CD40, CD80, and CD86), and the adhesion molecule CD54 (ICAM-1). rAd-transduced DC exhibited increased allostimulatory capacity and levels of interleukin-6 (IL-6), IL-12p40, IL-15, gamma interferon, and tumor necrosis factor alpha mRNAs, without effects on other immunoregulatory cytokine transcripts such as IL-10 or IL-12p35. These effects were not related to specific transgenic sequences or to rAd genome transcription. The rAd effect correlated with a rapid increase (1 h) in the NF-kappa B-DNA binding activity detected by electrophoretic mobility shift assays. rAd-induced DC maturation was blocked by the proteasome inhibitor Nalpha -p-tosyl-L-lysine chloromethyl ketone (TLCK) or by infection with rAd-Ikappa B, an rAd-encoding the dominant-negative form of Ikappa B. In vivo studies showed that after intravenous administration, rAds were rapidly entrapped in the spleen by marginal zone DC that mobilized to T-cell areas, a phenomenon suggesting that rAd also induced DC differentiation in vivo. These findings may explain the immunogenicity of rAd and the difficulties in inducing long-term antigen-specific T-cell hyporesponsiveness with rAd-transduced DC.

* Corresponding author. Mailing address: Department of Surgery, University of Pittsburgh Medical Center, E1504 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15213. Phone: (412) 624-6627. Fax: (412) 624-1172. E-mail: morelli{at}imap.pitt.edu.

Journal of Virology, October 2000, p. 9617-9628, Vol. 74, No. 20
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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