CRAC channel inhibition produces greater anti-inflammatory effects than glucocorticoids in CD8 cells from COPD patients.
CRAC channel inhibition produces greater anti-inflammatory effects than glucocorticoids in CD8 cells from COPD patients.
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DOI：
10.1042/cs20130152
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发表时间：
2014-02
期刊：
影响因子：
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通讯作者：
Singh D
中科院分区：
文献类型：
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作者：
Grundy S;Kaur M;Plumb J;Reynolds S;Hall S;House D;Begg M;Ray D;Singh D
COPD 患者肺部 CD8 淋巴细胞数量增加。钙释放激活钙 (CRAC) 通道通过调节活化 T 细胞的转录因子核因子 (NFAT) 在淋巴细胞激活中发挥核心作用。我们研究了 COPD 肺部与对照组相比的 NFAT 表达，并评估了与皮质类固醇相比 CRAC 抑制对 NFAT 激活和 COPD CD8 细胞产生细胞因子的影响。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 抑制剂 synta-66 对细胞因子产生和 NFAT 激活的影响。使用免疫组织化学和免疫荧光相结合的方法，比较了 COPD 和对照组肺中 NFAT1 和 CD8 的共表达。在外周血和肺部 CD8 细胞中，使用环孢菌素或 synta-66 抑制 NFAT 会比地塞米松产生显着更大的细胞因子最大抑制（例如，使用环孢菌素和 synta-66 对肺部 CD8 细胞产生 IFNγ 的抑制率 > 95%，而使用地塞米松则抑制 <50%）。与对照组相比，COPD 肺中共表达 NFAT1 的肺部 CD8 细胞的绝对数量显着增加，但 COPD 和对照组之间共表达 NFAT1 的 CD8 细胞的百分比相似（分别为 80.7 % 和 78.5 %，p = 0.3）。使用 CRAC 抑制剂 synta-66 抑制 NFAT 对 COPD CD8 细胞产生比皮质类固醇更强的抗炎作用。 NFAT 在高比例的 COPD 肺部 CD8 细胞中表达。
There are increased numbers of pulmonary CD8 lymphocytes in COPD. Calcium-release activation calcium (CRAC) channels play a central role in lymphocyte activation though the regulation of the transcription factor nuclear factor of activated T cells (NFAT). We studied the expression of NFAT in COPD lungs compared to controls, and evaluated the effects of CRAC inhibition compared to corticosteroids on NFAT activation and cytokine production from COPD CD8 cells. The effects of the corticosteroid dexamethasone, the calcineurin inhibitor cyclosporin and the CRAC 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 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 production from pulmonary CD8 cells using cyclosporin and synta-66 compared to <50% using dexamethasone). The absolute number of pulmonary CD8 cells co-expressing NFAT1 was significantly raised in COPD lung compared to controls, but the percentage of CD8 cells co-expressing NFAT1 was similar between COPD and controls (80.7 % vs 78.5 % respectively, p=0.3). Inhibition of NFAT using the CRAC inhibitor synta-66 produces greater anti-inflammatory effects on COPD CD8 cells than corticosteroids. NFAT is expressed in a high proportion of COPD pulmonary CD8 cells.