The combination of IκB kinase β inhibitor and everolimus modulates expression of interleukin-10 in human T-cell lymphotropic virus type-1-infected T cells

Authors

  • Chie Nishioka,

    1. Department of Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
    2. Japanese Society for the Promotion of Science (JSPS), Chiyoda-ku, Tokyo, Japan
    Search for more papers by this author
  • Takayuki Ikezoe,

    Corresponding author
    1. Department of Haematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
    • Department of Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
    Search for more papers by this author
  • Jing Yang,

    1. Department of Haematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
    Search for more papers by this author
  • Keiko Udaka,

    1. Department of Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
    Search for more papers by this author
  • Akihito Yokoyama

    1. Department of Haematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
    Search for more papers by this author

Correspondence: Takayuki Ikezoe, MD, Department of Haematology and Respiratory Medicine, Kochi University, Oko-cho, Nankoku, Kochi 783-8505, Japan. Email: ikezoet@kochi-u.ac.jp

Senior author: Akihito Yokoyama,email: oyama@kochi-u.ac.jp

Summary

Adult T-cell leukaemia-lymphoma (ATLL) is an aggressive malignancy of CD4+ CD25+ T lymphocytes, characterized by a severely compromised immunosystem, in which the human T-cell lymphotropic virus type 1 (HTLV-1) has been recognized as the aetiological agent. This study found that an IκB kinase β (IKKβ) inhibitor Bay11-7082 inactivated mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 and transcription factor nuclear factor-κB in HTLV-1-infected T cells; this was significantly enhanced in the presence of the mTOR inhibitor everolimus. In addition, Bay11-7082 decreased production of the immunosuppressive cytokine interleukin-10 (IL-10), which was further down-regulated when Bay11-7082 was combined with evelolimus in HTLV-1-infected T and ATLL cells isolated from patients. Interleukin-10 is known to inhibit maturation and the antigen-presenting function of dendritic cells (DCs). The culture media of HTLV-1-infected MT-1 cells, which contained a large amout of IL-10, hampered tumour necrosis factor-α-induced maturation of DCs isolated from healthy volunteers. Culture supernatant of MT-1 cells treated with a combination of Bay11-7082 and everolimus augmented maturation of DCs in association with a decrease in production of IL-10 and enhanced the allostimulatory function of DCs. Similarly, when DCs isolated from patients with ATLL were treated with the combination of Bay11-7082 and everolimus, they were fully matured and their capability to stimulate proliferation of lymphocytes was augmented. Taken together, the combination of Bay11-7082 and everolimus might exhibit immunostimulatory properties in HTLV-1-infected T and ATLL cells isolated from patients, and this combination may be potentially therapeutic to regain the compromised immunosystem in ATLL patients.

Ancillary