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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
Author(s) -
Nishioka Chie,
Ikezoe Takayuki,
Yang Jing,
Udaka Keiko,
Yokoyama Akihito
Publication year - 2013
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12035
Subject(s) - biology , cancer research , pi3k/akt/mtor pathway , virology , microbiology and biotechnology , signal transduction
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.