Increased caspase-3 expression and activity contribute to reduced CD3ζ expression in systemic lupus erythematosus T cells
Increased caspase-3 expression and activity contribute to reduced CD3ζ expression in systemic lupus erythematosus T cells
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DOI：
10.4049/jimmunol.175.5.3417
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发表时间：
2005-09-01
影响因子：
4.4
通讯作者：
Tsokos, GC
中科院分区：
文献类型：
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作者：
Krishnan, S;Kiang, JG;Tsokos, GC
从系统性红斑狼疮（SLE）患者中分离的T细胞表达低水平的CD3 xi-链，CD3 xi-链是参与tcr介导的信号传导的关键分子，但涉及的机制尚不完全清楚。在这项研究中，我们检测了caspase-3作为SLE T细胞中cd3xi的候选物。我们证明SLE T细胞显示caspase-3的表达和活性增加。用caspase-3抑制剂Z-Asp-Glu-Val-Asp-FMK治疗SLE T细胞可减少cd3xi的蛋白水解并增强其表达。此外，Z-Asp-Glu-Val-Asp-FMK处理增加了cd3xi与脂筏的关联，同时逆转了异常脂筏预聚类，增强了tcr诱导的钙反应，并降低了SLE T细胞中FcR γ链的表达。我们得出结论，caspase-3抑制剂可以通过限制CD3 x -链的过度消化来使SLE T细胞功能正常化，并建议在治疗这种疾病时可以考虑使用这些分子。
T cells isolated from patients with systemic lupus erythematosus (SLE) express low levels of CD3 xi-chain, a critical molecule involved in TCR-mediated signaling, but the involved mechanisms are not fully understood. In this study we examined caspase-3 as a candidate for cleaving CD3 xi in SLE T cells. We demonstrate that SLE T cells display increased expression and activity of caspase-3. Treatment of SLE T cells with the caspase-3 inhibitor Z-Asp-Glu-Val-Asp-FMK reduced proteolysis of CD3 xi and enhanced its expression. In addition, Z-Asp-Glu-Val-Asp-FMK treatment increased the association of CD3 xi with lipid rafts and simultaneously reversed the abnormal lipid raft preclustering, heightened TCR-induced calcium responses, and reduced the expression of FcR gamma-chain exclusively in SLE T cells. We conclude that caspase-3 inhibitors can normalize SLE T cell function by limiting the excessive digestion of CD3 xi-chain and suggest that such molecules can be considered in the treatment of this disease.