title: Selective induction of Th2-attracting chemokines CCL17 and CCL22 in human B cells by latent membrane protein 1 of Epstein-Barr virus.
abstract: 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-1 beta/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.
authors.affiliation: Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakayama
authors.forename: Kunio
authors.initials: K
authors.lastname: Hieshima
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagakubo
authors.forename: Emiko
authors.initials: E
authors.lastname: Sato
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakayama
authors.forename: Keisei
authors.initials: K
authors.lastname: Kawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshie
mesh_terms: D001402:B-Lymphocytes / Q000821:virology*; D001782:Blood Donors; D002461:Cell Line, Transformed; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007244:Infectious Mononucleosis / Q000276:immunology / Q000821:virology; D018418:Th2 Cells / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology*
chemical_list: C106230:CCL17 protein, human; C515482:CCL22 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D018925:Chemokines; D019742:Chemokines, CC; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins