title: 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.
abstract: 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.
authors.affiliation: Department of Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Keiko
authors.initials: K
authors.lastname: Udaka
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects; D000068338:Everolimus; D005786:Gene Expression Regulation / Q000187:drug effects*; D015490:HTLV-I Infections / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D009570:Nitriles; D050796:STAT3 Transcription Factor; D013450:Sulfones; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase; D020123:Sirolimus