Constitutive Activation of Interleukin-13/STAT6 Contributes to Kaposi's Sarcoma-Associated Herpesvirus-Related Primary Effusion Lymphoma Cell Proliferation and Survival

J Virol. 2015 Oct;89(20):10416-26. doi: 10.1128/JVI.01525-15. Epub 2015 Aug 5.

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.

Importance: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / pharmacology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • B-Lymphocytes / virology*
  • Cell Cycle / genetics
  • Cell Cycle / immunology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Gene Expression Regulation*
  • HEK293 Cells
  • Herpesvirus 8, Human / genetics*
  • Herpesvirus 8, Human / immunology
  • Host-Pathogen Interactions
  • Humans
  • Interleukin-13 / antagonists & inhibitors
  • Interleukin-13 / genetics
  • Interleukin-13 / immunology*
  • Janus Kinase 1 / genetics
  • Janus Kinase 1 / immunology
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / immunology
  • Lymphoma, Primary Effusion / genetics
  • Lymphoma, Primary Effusion / immunology
  • Lymphoma, Primary Effusion / pathology
  • Lymphoma, Primary Effusion / virology
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology
  • STAT6 Transcription Factor / genetics
  • STAT6 Transcription Factor / immunology*
  • Sarcoma, Kaposi / genetics
  • Sarcoma, Kaposi / immunology
  • Sarcoma, Kaposi / pathology
  • Sarcoma, Kaposi / virology
  • Signal Transduction
  • Virion / genetics
  • Virion / immunology
  • Virus Latency

Substances

  • Antibodies, Neutralizing
  • Interleukin-13
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • interleukin-13, human
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6