Aspartic protease and caspase 3/7 activation are central for macrophage apoptosis following infection with Escherichia coli
Aspartic protease and caspase 3/7 activation are central for macrophage apoptosis following infection with Escherichia coli
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DOI：
10.1189/jlb.0506358
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发表时间：
2007-01-01
影响因子：
5.5
通讯作者：
Perlman, Harris
中科院分区：
文献类型：
--
作者：
Albee, Lee;Shi, Bo;Perlman, Harris
巨噬细胞对宿主抵御微生物感染至关重要。我们之前的研究表明，非致病性大肠杆菌感染巨噬细胞可迅速诱导细胞凋亡。在这里，我们证明了巨噬细胞的感染导致半胱天蛋白酶的激活，而不是诱导内在凋亡途径。在感染的巨噬细胞中，caspase 9和caspase 3在膜间线粒体蛋白细胞色素C释放到细胞质之前被激活。用caspase 9抑制剂治疗对巨噬细胞的死亡没有影响，也不会阻止下游效应caspase 3/7的激活。相反，caspase 3/7抑制剂可减少大肠杆菌感染巨噬细胞的细胞死亡。虽然caspase 9不是必需的，但天冬氨酸蛋白酶的激活对于caspase 3/7的激活是必不可少的，其中组织蛋白酶D是中心成员之一。用胃抑素A（一种天冬氨酸蛋白酶抑制剂）治疗可显著降低组织蛋白酶D和半胱天冬酶3/7的活化，减少大肠杆菌感染巨噬细胞的死亡。总的来说，这些数据表明，组织蛋白酶D激活caspase 3/7可能需要诱导大肠杆菌引发的一种死亡途径。
Macrophages are vital for host defense against microbial infections. We have previously shown that infection of macrophages with a nonpathogenic strain of Escherichia coli induces apoptosis rapidly. Here, we demonstrate that infection of macrophages results in the activation of caspases prior to the induction of the intrinsic apoptosis pathway. Caspases 9 and 3 are activated prior to the release of intermembrane mitochondrial protein cytochrome C into the cytosol in infected macrophages. Treatment with an inhibitor to caspase 9 has no effect on the death of macrophages and does not prevent activation of the downstream effector caspase 3/7. In contrast, an inhibitor to caspase 3/7 reduces cell death in E. coli-infected macrophages. Although caspase 9 is not required, activation of aspartic proteases, of which cathepsin D is one of the central members, is essential for activation of caspase 3/7. Treatment with pepstatin A, an inhibitor of aspartic proteases, markedly diminishes the activation of cathepsin D and caspase 3/7 and reduces death in E. coli-infected macrophages. Collectively, these data suggest that cathepsin D activation of caspase 3/7 may be required for inducing one of the death pathways elicited by E. coli.