Overexpression of heme oxygenase (HO)-1 renders Jurkat T cells resistant to Fas-mediated apoptosis: Involvement of iron released by HO-1
Overexpression of heme oxygenase (HO)-1 renders Jurkat T cells resistant to Fas-mediated apoptosis: Involvement of iron released by HO-1
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DOI：
10.1016/j.freeradbiomed.2004.01.004
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发表时间：
2004-04-01
影响因子：
7.4
通讯作者：
Chung, HT
中科院分区：
文献类型：
--
作者：
Choi, BM;Pae, HO;Chung, HT
我们最近证实，血红素加氧酶(HO)-1在人CD4(+)CD25(+)调节性T细胞中有结构性表达，并在抗CD28或抗CD28/抗CD3刺激下被诱导，甚至在CD4(+)CD25(-)应答T细胞中也是如此。为了研究HO-1表达对淋巴细胞存活的影响，我们将HO-1基因导入Jurkat T细胞，或用钴原卟啉(CoPP)诱导该基因表达HO-1蛋白。一直以来，抗Fas抗体在野生型Jurkat T细胞中引发了细胞死亡。然而，令人惊讶的是，HO-1过表达的Jurkat T细胞对Fas介导的细胞凋亡表现出很强的抵抗力。相反，COPP处理的细胞中针对HO-1基因的反义寡聚体消除HO-1的表达，或去铁胺去除HO-1转基因细胞中的铁消除耐药性。此外，外源性添加的铁使野生型Jurkat T细胞产生抗药性。这种抗性包括铁诱导的活性氧生成激活IkappaB激酶(IKK)，激活的IKK激活核因子-kappaB，激活的核因子-kappaB激活c-flip。经CoPP诱导表达HO-1的原代CD4(+)T细胞对Fas介导的细胞凋亡也表现出比未处理细胞更强的抵抗力。我们的研究结果表明，HO-1在Fas介导的活化诱导的T淋巴细胞细胞死亡中起着关键的和非冗余的作用。(C)2004 Elsevier Inc.保留所有权利。
We recently demonstrated that heme oxygenase (HO)-1 is constitutively expressed in human CD4(+)CD25(+) regulatory T cells and induced by anti-CD28 or anti-CD28/anti-CD3 stimulation, even in CD4(+)CD25(-) responder T cells. To study the effects of HO-1 expression on lymphocyte survival, we transfected the HO-1 gene or induced the gene to express HO-1 protein with cobalt protoporphyrin (CoPP) in Jurkat T cells. Consistently, anti-Fas antibody triggered apoptotic cell death in wild-type Jurkat T cells. Surprisingly, however, HO-1-overexpressing Jurkat T cells showed strong resistance to Fas-mediated apoptosis. In contrast, abrogation of HO-1 expression by antisense oligomer against HO-1 gene from CoPP-treated cells or depletion of iron by desferrioxamine from HO-1-transfected cells abolished the resistance. In addition, exogenously added iron rendered wild-type Jurkat T cells resistant. The resistance involved IkappaB kinase (IKK) activation via iron-induced reactive oxygen species formation, NF-kappaB activation by activated IKK, and c-FLIP expression by activated NF-kappaB. Primary CD4(+) T cells induced by CoPP to express HO-1 also showed more resistance to Fas-mediated apoptosis than untreated cells. Our findings suggest that HO-1 plays a critical and nonredundant role in Fas-mediated activation-induced cell death of T lymphocytes. (C) 2004 Elsevier Inc. All rights reserved.