title: Autocrine CCL3 and CCL4 induced by the oncoprotein LMP1 promote Epstein-Barr virus-triggered B cell proliferation.
abstract: Epstein-Barr virus (EBV) alters the regulation and expression of a variety of cytokines in its host cells to modulate host immune surveillance and facilitate viral persistence. Using cytokine antibody arrays, we found that, in addition to the cytokines reported previously, two chemotactic cytokines, CCL3 and CCL4, were induced in EBV-infected B cells and were expressed at high levels in all EBV-immortalized lymphoblastoid cell lines (LCLs). Furthermore, EBV latent membrane protein 1 (LMP1)-mediated Jun N-terminal protein kinase activation was responsible for upregulation of CCL3 and CCL4. Inhibition of CCL3 and CCL4 in LCLs using a short hairpin RNA approach or by neutralizing antibodies suppressed cell proliferation and caused apoptosis, indicating that autocrine CCL3 and CCL4 are required for LCL survival and growth. Importantly, significant amounts of CCL3 were detected in EBV-positive plasma from immunocompromised patients, suggesting that EBV modulates this chemokine in vivo. This study reveals the regulatory mechanism and a novel function of CCL3 and CCL4 in EBV-infected B cells. CCL3 might be useful as a therapeutic target in EBV-associated lymphoproliferative diseases and malignancies.
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Tsai
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Lin
authors.forename: Cheau-Jye
authors.initials: CJ
authors.lastname: Lin
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Chou
authors.forename: Jiun-Han
authors.initials: JH
authors.lastname: Lin
authors.forename: Te-Huei
authors.initials: TH
authors.lastname: Yeh
authors.forename: Mei-Ru
authors.initials: MR
authors.lastname: Chen
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Huang
authors.forename: Meng-You
authors.initials: MY
authors.lastname: Lu
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Huang
authors.forename: Huan-Yun
authors.initials: HY
authors.lastname: Chen
authors.forename: Ching-Hwa
authors.initials: CH
authors.lastname: Tsai
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology / Q000821:virology*; D049109:Cell Proliferation; D054405:Chemokine CCL3 / Q000096:biosynthesis*; D054407:Chemokine CCL4 / Q000096:biosynthesis*; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000378:metabolism*
chemical_list: C515429:CCL3 protein, human; C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D048031:JNK Mitogen-Activated Protein Kinases