Specific involvement of caspases in the differentiation of monocytes into macrophages
Specific involvement of caspases in the differentiation of monocytes into macrophages
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DOI：
10.1182/blood-2002-06-1778
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发表时间：
2002-12-15
期刊：
影响因子：
20.3
通讯作者：
Dubrez-Daloz, L
中科院分区：
文献类型：
--
作者：
Sordet, O;Rébé, C;Dubrez-Daloz, L
半胱氨酸蛋白酶是参与细胞凋亡和细胞因子成熟的半胱氨酸蛋白酶。在分化的成红细胞、角质形成细胞和透镜上皮细胞中，去核被认为是半胱天冬酶介导的不完全凋亡过程。在这里，我们表明，几个半胱天冬酶激活人外周血单核细胞分化成巨噬细胞诱导的巨噬细胞集落刺激因子（M-CSF）。这种激活与细胞死亡无关，并且在白细胞介素-4（IL-4）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）存在下经历树突状细胞分化的单核细胞中无法检测到。在经历佛波酯诱导分化成巨噬细胞的U937人单核细胞中进一步研究半胱天冬酶激活的机制和后果。分化相关的半胱天冬酶激活涉及从线粒体释放细胞色素c，并导致蛋白质腺泡的切割，而聚（ADP-核糖）聚合酶保持未切割。通过暴露于广谱抑制剂苄氧基羰基-Val-Ala-（DL）-Asp-氟-甲基酮（z-VAD-fetoxin）或表达p35杆状病毒抑制蛋白或过表达Bcl-2来抑制半胱天冬酶抑制分化过程。此外，z-VAD-fetamine放大了佛波酯分化的U937细胞和M-CSF处理的单核细胞中自由基氧物种的分化相关产生，将分化过程转变为非凋亡性细胞死亡。总之，这些结果表明，在没有细胞死亡的情况下，胱天蛋白酶活化特别有助于单核细胞分化为巨噬细胞。
Caspases are cysteine proteases involved in apoptosis and cytokine maturation. In erythroblasts, keratinocytes, and lens epithelial cells undergoing differentiation, enucleation has been regarded as a caspase-mediated incomplete apoptotic process. Here, we show that several caspases are activated in human peripheral blood monocytes whose differentiation into macrophages is induced by macrophage colony-stimulating factor (M-CSF). This activation is not associated with cell death and cannot be detected in monocytes undergoing dendritic cell differentiation in the presence of interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The mechanisms and consequences of caspase activation were further studied in U937 human monocytic cells undergoing phorbol ester-induced differentiation into macrophages. Differentiation-associated caspase activation involves the release of cytochrome c from the mitochondria and leads to the cleavage of the protein acinus while the poly(ADP-ribose)polymerase remains uncleaved. Inhibition of caspases by either exposure to the broad-spectrum inhibitor benzyloxycarbonyl-Val-Ala-(DL)-Asp-fluoro-methylketone (z-VAD-fmk) or expression of the p35 baculovirus inhibitory protein or overexpression of Bcl-2 inhibits the differentiation process. In addition, z-VAD-fmk amplifies the differentiation-associated production of radical oxygen species in both phorbol ester-differentiated U937 cells and M-CSF-treated monocytes, shifting the differentiation process to nonapoptotic cell death. Altogether, these results indicate that caspase activation specifically contributes to the differentiation of monocytes into macrophages, in the absence of cell death.