*University of Manchester NIHR Translational Research Facility, Manchester Academic Health Science Centre, University Hospital of South Manchester Foundation Trust, Manchester M23 9LT, U.K.
Clin Sci (Lond). 2014 Feb;126(3):223-32. doi: 10.1042/CS20130152.
There are increased numbers of pulmonary CD8 lymphocytes in COPD (chronic obstructive pulmonary disease). CRAC (calcium release-activation calcium) channels play a central role in lymphocyte activation though the regulation of the transcription factor NFAT (nuclear factor of activated T-cells). We studied the expression of NFAT in lungs from COPD patients compared with controls, and evaluated the effects of CRAC channel inhibition compared with corticosteroids on NFAT activation and cytokine production in CD8 cells from COPD patients. The effects of the corticosteroid dexamethasone, the calcineurin inhibitor cyclosporin and the CRAC channel inhibitor Synta 66 were studied on cytokine production and NFAT activation using peripheral blood and isolated pulmonary CD8 cells. NFAT1 and CD8 co-expression in the lungs was compared in COPD patients and controls using combined immunohistochemistry and immunofluorescence. NFAT inhibition with either cyclosporin or Synta 66 resulted in significantly greater maximal inhibition of cytokines than dexamethasone in both peripheral blood and pulmonary CD8 cells [e.g. >95% inhibition of IFNγ (interferon γ) production from pulmonary CD8 cells using cyclosporin and Synta 66 compared with <50% using dexamethasone]. The absolute number of pulmonary CD8 cells co-expressing NFAT1 was significantly raised in lungs from COPD patients compared with controls, but the percentage of CD8 cells co-expressing NFAT1 was similar between COPD patients and controls (80.7% compared with 78.5% respectively, P=0.3). Inhibition of NFAT using the CRAC channel Synta 66 produces greater anti-inflammatory effects on CD8 cells from COPD patients than corticosteroids. NFAT is expressed at a high level in pulmonary CD8 cells in COPD.
在 COPD（慢性阻塞性肺疾病）患者中，肺部的 CD8 淋巴细胞数量增加。CRAC（钙释放激活钙）通道通过调节转录因子 NFAT（活化 T 细胞的核因子）在淋巴细胞激活中发挥核心作用。我们研究了 COPD 患者与对照组相比，NFAT 在肺部的表达，并评估了 CRAC 通道抑制剂与皮质类固醇对 COPD 患者 CD8 细胞中 NFAT 激活和细胞因子产生的影响。使用外周血和分离的肺 CD8 细胞，研究了皮质类固醇地塞米松、钙调神经磷酸酶抑制剂环孢素和 CRAC 通道抑制剂 Synta 66 对细胞因子产生和 NFAT 激活的影响。使用组合免疫组织化学和免疫荧光技术比较了 COPD 患者和对照组肺部 NFAT1 和 CD8 的共表达。环孢素或 Synta 66 抑制 NFAT 导致外周血和肺 CD8 细胞中细胞因子的最大抑制作用明显大于地塞米松[例如，使用环孢素和 Synta 66 从肺 CD8 细胞中抑制 IFNγ（干扰素 γ）产生>95％，而使用地塞米松<50％]。与对照组相比，COPD 患者肺部共表达 NFAT1 的肺 CD8 细胞数量明显增加，但 COPD 患者和对照组之间 CD8 细胞共表达 NFAT1 的百分比相似（分别为 80.7％和 78.5％，P=0.3）。使用 CRAC 通道 Synta 66 抑制 NFAT 对 COPD 患者的 CD8 细胞产生比皮质类固醇更强的抗炎作用。NFAT 在 COPD 患者的肺 CD8 细胞中高表达。
