title: Constitutive Activation of Interleukin-13/STAT6 Contributes to Kaposi's Sarcoma-Associated Herpesvirus-Related Primary Effusion Lymphoma Cell Proliferation and Survival.
abstract: Activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway has been associated with numerous human malignancies, including primary effusion lymphomas (PELs). PEL, a cancerous proliferation of B cells, is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Previously we identified constitutive phosphorylation of STAT6 on tyrosine 641 (p-STAT6(C)) in PEL cell lines BC3 and BCBL1; however, the molecular mechanism leading to this activation remains unclear. Here we demonstrate that STAT6 activation tightly correlates with interleukin-13 (IL-13) secretion, JAK1/2 tyrosine phosphorylation, and reduced expression of SHP1 due to KSHV infection. Moreover, p-STAT6(C) and reduction of SHP1 were also observed in KS patient tissue. Notably, blockade of IL-13 by antibody neutralization dramatically inhibits PEL cell proliferation and survival. Taken together, these results suggest that IL-13/STAT6 signaling is modulated by KSHV to promote host cell proliferation and viral pathogenesis.
  
  
  OBJECTIVE
  STAT6 is a member of signal transducer and activator of transcription (STAT) family, whose activation is linked to KSHV-associated cancers. The mechanism through which STAT6 is modulated by KSHV remains unclear. In this study, we demonstrated that constitutive activation of STAT6 in KSHV-associated PEL cells results from interleukin-13 (IL-13) secretion and reduced expression of SHP1. Importantly, we also found that depletion of IL-13 reduces PEL cell growth and survival. This discovery provides new insight that IL-13/STAT6 plays an essential role in KSHV pathogenesis.
authors.affiliation: MOE & MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.affiliation: MOE & MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Zhu
authors.affiliation: ShengYushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wei
authors.affiliation: MOE & MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.affiliation: MOE & MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Feng
authors.affiliation: MOE & MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
authors.affiliation: MOE & MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Microbiology and Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Erle
authors.initials: E
authors.lastname: Robertson
authors.affiliation: MOE & MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China qiliang@fudan.edu.cn.
authors.forename: Qiliang
authors.initials: Q
authors.lastname: Cai
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology*; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D053613:Janus Kinase 1 / Q000235:genetics / Q000276:immunology; D053614:Janus Kinase 2 / Q000235:genetics / Q000276:immunology; D054685:Lymphoma, Primary Effusion / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000276:immunology; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology*; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D014771:Virion / Q000235:genetics / Q000276:immunology; D017735:Virus Latency
chemical_list: D057134:Antibodies, Neutralizing; C578095:IL13 protein, human; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6