Zinc signals promote IL-2-dependent proliferation of T cells
Zinc signals promote IL-2-dependent proliferation of T cells
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DOI：
10.1002/eji.200939574
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发表时间：
2010-05-01
影响因子：
5.4
通讯作者：
Haase, Hajo
中科院分区：
文献类型：
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作者：
Kaltenberg, Jennifer;Plum, Laura M.;Haase, Hajo
锌信号，即细胞内游离锌离子浓度响应受体刺激的变化，参与多种免疫细胞的信号转导。本研究在小鼠细胞毒性T细胞系CTLL-2和人原代T细胞中研究了锌信号在IL-2激活T细胞中的作用。荧光染料FluoZin-3和Zinquin的测定表明，在il -2受体的刺激下，锌从溶酶体释放到细胞质中。游离锌与N，N，N‘，N’-tetrakis-2（pyridyl-methyl）乙二胺螯合可阻断erk通路的激活，而STAT5磷酸化不需要锌。此外，关键信号分子MEK和ERK在细胞内游离锌升高的情况下被激活，这是由锌和离子载体吡硫酮引起的。在ERK激活的下游，c-fos和il -2诱导的ERK特异性基因表达依赖于锌。进一步的实验表明，抑制MEK和erk去磷酸化蛋白磷酸酶是锌影响该途径的分子机制。综上所述，il -2诱导的ERK信号和T细胞的增殖需要细胞质游离锌的增加。
Zinc signals, i.e. a change of the intracellular concentration of free zinc ions in response to receptor stimulation, are involved in signal transduction in several immune cells. Here, the role of zinc signals in T-cell activation by IL-2 was investigated in the murine cytotoxic T-cell line CTLL-2 and in primary human T cells. Measurements with the fluorescent dyes FluoZin-3 and Zinquin showed that zinc is released from lysosomes into the cytosol in response to stimulation of the IL-2-receptor. Activation of the ERK-pathway was blocked by chelation of free zinc with N,N,N',N'-tetrakis-2(pyridyl-methyl)ethylenediamine, whereas zinc was not required for STAT5 phosphorylation. In addition, the key signaling molecules MEK and ERK were activated in response to elevated free intracellular zinc, induced by incubation with zinc and the ionophore pyrithione. Downstream of ERK activation, ERK-specific gene expression of c-fos and IL-2-induced proliferation was found to depend on zinc. Further experiments indicated that inhibition of MEK and ERK-dephosphorylating protein phosphatases is the molecular mechanism for the influence of zinc on this pathway. In conclusion, an increase of cytoplasmic free zinc is required for IL-2-induced ERK signaling and proliferation of T cells.