TNFR1-induced sphingomyelinase activation modulates TCR signaling by impairing store-operated Ca2+ influx
TNFR1-induced sphingomyelinase activation modulates TCR signaling by impairing store-operated Ca2+ influx
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DOI：
10.1189/jlb.1003456
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发表时间：
2005-07-01
影响因子：
5.5
通讯作者：
Young, SP
中科院分区：
文献类型：
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作者：
Church, LD;Hessler, G;Young, SP
肿瘤坏死因子α（TNF-α）是一种强效的多效细胞因子，具有促炎作用，但也可抑制T淋巴细胞功能。在慢性炎症性疾病如类风湿性关节炎中，T细胞暴露于TNF-α通过调节T细胞受体（TCR）信号通路改变了它们产生应答的能力，但所涉及的机制仍然不清楚。在这里，我们研究了肿瘤坏死因子受体1（TNFR 1）信号在TCR信号通路的调制的具体作用。我们观察到Jurkat T细胞在TNF-α暴露30分钟后细胞内钙（[Ca 2 +]（i））信号下调，3小时后达到最大抑制。这种效应是短暂的，12小时后信号恢复正常。在人CD 4 + T淋巴细胞中也观察到这种[Ca 2 +]（i）的抑制。Ca 2+信号的变化与质膜Ca 2+内流的减少有关，即使当使用毒胡萝卜素绕过TCR信号以诱导Ca 2+内流时，这也是明显的。研究了TNF-α诱导的鞘脂级联激活在该途径中的作用。TNF-α与TNFR 1的结合导致酸性鞘磷脂酶（SMase; ASM）活性的时间依赖性增加，与细胞鞘磷脂的减少相对应。与此同时，细胞神经酰胺增加，这与植物血镁素的钙离子响应幅度的降低直接相关。外源性添加SMase或神经酰胺模拟TNFR 1信号对Jurkat T细胞中Ca 2+应答的影响。通过完全消除TNF-α诱导的对ASM缺陷型鼠T细胞系（OT-II（+/+）ASM（-/-））中Ca 2+内流的抑制，提供了该途径中ASM活化的直接证据。TNF-α通过TNFR 1诱导的ASM活化快速调节TCR Ca 2+信号的这种有效能力可以解释其对T细胞功能的抑制作用。这种TNFR 1信号通路可能作为T细胞应答的重要调节剂发挥作用。
Tumor necrosis factor alpha (TNF-alpha) is a potent, pleiotrophic cytokine, which is proinflammatory but can also suppress T lymphocyte function. In chronic inflammatory disease such as rheumatoid arthritis, exposure of T cells to TNF-alpha alters their ability to mount a response by modulating the T cell receptor (TCR) signaling pathway, but the mechanisms involved remain obscure. Here, we investigated the specific role of TNF receptor 1 (TNFR1) signaling in the modulation of the TCR signaling pathway. We observed a down-regulation of the intracellular calcium ([Ca2+](i)) signal in Jurkat T cells after just 30 min exposure to TNF-alpha, and maximum suppression was reached after 3 h. This effect was transient, and signals returned to normal after 12 h. This depression of [Ca2+](i) was also observed in human CD4+ T lymphocytes. The change in Ca2+ signal was related to a decrease in the plasma membrane Ca2+ influx, which was apparent even when the TCR signal was bypassed using thapsigargin to induce a Ca2+ influx. The role of TNF-alpha-induced activation of the sphingolipid cascade in this pathway was examined. The engagement of TNFR1 by TNF-alpha led to a time-dependent increase in acid sphingomyelinase (SMase; ASM) activity, corresponding with a decrease in cellular sphingomyelin. In parallel, there was an increase in cellular ceramide, which correlated directly with the decrease in the magnitude of the Ca2+ response to phytohemagglutftiin. Exogenous addition of SMase or ceramide mimicked the effects of TNFR1 signals on Ca2+ responses in Jurkat T cells. Direct evidence for the activation of ASM in this pathway was provided by complete abrogation of the TNF-alpha-induced inhibition of the Ca2+ influx in an ASM-deficient murine T cell line (OT-II(+/+)ASM(-/-)). This potent ability of TNF-alpha to rapidly modulate the TCR Ca2+ signal via TNFR1-induced ASM activation can explain its suppressive effect on T cell function. This TNFR1 signaling pathway may play a role as an important regulator of T cell responses.