Mori A, Suko M, Kaminuma O, Inoue S, Ohmura T, Hoshino A, Asakura Y, Terada E, Miyazawa K, Nosaka C, Okumura Y, Ito K, Okudaira H
Department of Medicine, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Japan.
J Immunol. 1997 Apr 15;158(8):3659-65.
Regulation of T cell IL-5 synthesis was investigated using human Th cell clones. Immunosuppressant FK506 suppressed IL-5 synthesis of T cells activated through TCR in a dose-dependent manner. IL-5 gene transcription and protein synthesis were also induced in the same T cell clones upon stimulation with IL-2 and were suppressed by FK506 in a dose response similar to that induced by TCR stimulation. In contrast to TCR stimulation, neither activating protein-1, nuclear factor-AT (NF-AT), nor NF-kappaB binding activity was significantly up-regulated by IL-2 stimulation. Human IL-5 promoter/enhancer-luciferase gene construct transfected to T cell clones was transcribed upon either TCR or IL-2 stimulation and was clearly down-regulated by FK506, indicating that the approximately 500-bp human IL-5 gene segment located 5' upstream of the coding region contained FK506-sensitive enhancer elements. Our present findings clearly indicate that FK506-sensitive signaling molecules are involved in T cell IL-5 production induced by both TCR and IL-2 stimulation and suggest that IL-2 receptor signal leading to IL-5 gene transcription is transduced by a unique FK506-sensitive pathway other than the Ca2+-dependent signal transduction pathway, such as the calcineurin-NF-AT system.
利用人Th细胞克隆研究了T细胞IL-5合成的调控。免疫抑制剂FK506以剂量依赖的方式抑制通过TCR激活的T细胞的IL-5合成。在用IL-2刺激时，相同的T细胞克隆中也诱导了IL-5基因转录和蛋白质合成，并且FK506以与TCR刺激诱导的相似的剂量反应抑制了它们。与TCR刺激相反，IL-2刺激并未显著上调激活蛋白-1、核因子-AT（NF-AT）或NF-κB的结合活性。转染到T细胞克隆中的人IL-5启动子/增强子-荧光素酶基因构建体在TCR或IL-2刺激时均被转录，并且明显被FK506下调，这表明位于编码区上游5'的约500bp人IL-5基因片段包含FK506敏感的增强子元件。我们目前的研究结果清楚地表明，FK506敏感的信号分子参与了由TCR和IL-2刺激诱导的T细胞IL-5产生，并表明导致IL-5基因转录的IL-2受体信号是通过不同于Ca2+依赖信号转导途径（如钙调神经磷酸酶-NF-AT系统）的独特的FK506敏感途径转导的。
