Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
J Biol Chem. 2011 Jun 17;286(24):21092-9. doi: 10.1074/jbc.M110.200907. Epub 2011 Apr 15.
Investigation of helper T cell markers in HTLV-1-transformed cell lines demonstrated that HuT-102 has an IL-9-producing Th17 phenotype. We confirmed the vital role of retinoic acid-related orphan receptor C, a Th17 transcription factor, in the expression of IL-17. Interferon regulatory factor 4 (IRF4), a transcription factor overexpressed in all HTLV-1-infected cells, regulated IL-17 and IL-9 concomitantly. We further demonstrated a novel pathway for the regulation of Tax-induced cytokines, IL-9 and IL-6, through TAK1-mediated nuclear accumulation of c-Rel. A microarray analysis for IRF4 knocked down HuT-102 cells showed a significant up-regulation in the set of genes related to Th1, mainly IFN-γ and several transcription factors. T-bet and IRF1, but not STAT1 and IRF9, participated in counteracting the inhibitory effect of IRF4 on the production of IFN-γ. Finally, suppression of both IRF4 and c-Rel resulted in the reduced proliferation. Collectively, these findings indicate that TAK1-c-Rel and IRF4 pathways play distinct roles in the maintenance of IL-9-producing Th17 phenotype of HTLV-1-transformed cells.
在 HTLV-1 转化细胞系中辅助性 T 细胞标志物的研究表明，HuT-102 具有产生 IL-9 的 Th17 表型。我们证实了 Th17 转录因子维甲酸相关孤儿受体 C 在 IL-17 表达中的重要作用。干扰素调节因子 4（IRF4）是一种在所有 HTLV-1 感染细胞中过度表达的转录因子，同时调节 IL-17 和 IL-9 的表达。我们进一步证明了 Tax 诱导的细胞因子（IL-9 和 IL-6）通过 TAK1 介导的 c-Rel 核积累的调节的新途径。针对 IRF4 敲低的 HuT-102 细胞进行的微阵列分析显示，与 Th1 相关的一组基因显著上调，主要是 IFN-γ 和几种转录因子。T-bet 和 IRF1，但不是 STAT1 和 IRF9，参与了拮抗 IRF4 对 IFN-γ 产生的抑制作用。最后，抑制 IRF4 和 c-Rel 均导致增殖减少。总之，这些发现表明 TAK1-c-Rel 和 IRF4 途径在维持 HTLV-1 转化细胞产生 IL-9 的 Th17 表型中发挥不同的作用。
