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Journal of Virology, February 2004, p. 1665-1674, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1665-1674.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Selective Induction of Th2-Attracting Chemokines CCL17 and CCL22 in Human B Cells by Latent Membrane Protein 1 of Epstein-Barr Virus

Takashi Nakayama,1 Kunio Hieshima,1 Daisuke Nagakubo,1 Emiko Sato,2 Masahiro Nakayama,2 Keisei Kawa,2 and Osamu Yoshie1*

Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511,1 Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi City, Osaka 594-1101, Japan2

Received 11 August 2003/ Accepted 27 October 2003

Chemokines are likely to play important roles in the pathophysiology of diseases associated with Epstein-Barr virus (EBV). Here, we have analyzed the repertoire of chemokines expressed by EBV-infected B cells. EBV infection of B cells induced expression of TARC/CCL17 and MDC/CCL22, which are known to attract Th2 cells and regulatory T cells via CCR4, and also upregulated constitutive expression of MIP-1{alpha}/CCL3, MIP-1ß/CCL4, and RANTES/CCL5, which are known to attract Th1 cells and cytotoxic T cells via CCR5. Accordingly, EBV-immortalized B cells secreted these chemokines, especially CCL3, CCL4, and CCL22, in large quantities. EBV infection or stable expression of LMP1 also induced CCL17 and CCL22 in a B-cell line, BJAB. The inhibitors of the TRAF/NF-{kappa}B pathway (BAY11-7082) and the p38/ATF2 pathway (SB202190) selectively suppressed the expression of CCL17 and CCL22 in EBV-immortalized B cells and BJAB-LMP1. Consistently, transient-transfection assays using CCL22 promoter-reporter constructs demonstrated that two NF-{kappa}B sites and a single AP-1 site were involved in the activation of the CCL22 promoter by LMP1. Finally, serum CCL22 levels were significantly elevated in infectious mononucleosis. Collectively, LMP1 induces CCL17 and CCL22 in EBV-infected B cells via activation of NF-{kappa}B and probably ATF2. Production of CCL17 and CCL22, which attract Th2 and regulatory T cells, may help EBV-infected B cells evade immune surveillance by Th1 cells. However, the concomitant production of CCL3, CCL4, and CCL5 by EBV-infected B cells may eventually attract Th1 cells and cytotoxic T cells, leading to elimination of EBV-infected B cells at latency III and to selection of those with limited expression of latent genes.


* Corresponding author. Mailing address: Department of Microbiology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan. Phone and fax: 81-(0)723-67-3606. E-mail: o.yoshie{at}med.kindai.ac.jp.


Journal of Virology, February 2004, p. 1665-1674, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1665-1674.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.




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