The combination of IκB kinase β inhibitor and everolimus modulates expression of inter leukin-10 in human T-cell lymphotropic virus type-1-infected T cells.
The combination of IκB kinase β inhibitor and everolimus modulates expression of inter leukin-10 in human T-cell lymphotropic virus type-1-infected T cells.
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IκB 激酶 β 抑制剂和依维莫司的组合可调节人 T 细胞嗜淋巴细胞病毒 1 型感染的 T 细胞中白细胞介素 10 的表达。
DOI：
10.1111/imm.12035
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Nishioka C
中科院分区：
文献类型：
--
作者：
中村壮智;他7名;Nishioka C;Yang J;Nishioka C
成人T细胞白血病-淋巴瘤(ATLL)是一种以免疫系统严重受损为特征的CD4+CD25+T淋巴细胞的侵袭性恶性肿瘤，人类T细胞嗜淋巴病毒1型(HTLV-1)是其病因之一。这项研究发现，IκB激酶β(IKKβ)抑制剂BA11-7082可使哺乳动物靶标雷帕霉素(MTor)、信号转导和转录激活因子3以及转录因子核因子κB在HTLV-1感染的T细胞中失活；在mTOR抑制剂埃博利马的存在下，这一作用显著增强。此外，Bay11-7082还减少了免疫抑制细胞因子IL-10的产生，当Bay11-7082与Evelolimus联合应用于HTLV-1感染的T和ATLL细胞时，IL-10的表达进一步下调。已知白介素10抑制树突状细胞(DC)的成熟和抗原提呈功能。含有大量IL-10的HTLV-1感染MT-1细胞的培养液抑制了肿瘤坏死因子-α诱导的健康志愿者DC的成熟。经Bay11-7082和伊波利莫联合作用的MT-1细胞培养上清液可促进DC的成熟，同时减少IL-10的产生，增强DC的同种异体刺激功能。同样，从ATLL患者分离的DC经Bay11-7082和伊波利莫斯联合作用后，其成熟完全，其刺激淋巴细胞增殖的能力增强。综上所述，Bay11-7082和依维莫司可能对HTLV-1感染的T细胞和从患者分离的ATLL细胞表现出免疫刺激特性，这种联合可能对ATLL患者恢复受损的免疫系统具有潜在的治疗作用。
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.