Inhibition of proteasome activity is involved in cobalt-induced apoptosis of human alveolar macrophages
Inhibition of proteasome activity is involved in cobalt-induced apoptosis of human alveolar macrophages
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DOI：
10.1152/ajplung.00422.2001
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发表时间：
2002-10-01
影响因子：
4.9
通讯作者：
Kobayashi, M
中科院分区：
文献类型：
--
作者：
Araya, J;Maruyama, M;Kobayashi, M
已知吸入微粒钴会诱发间质性肺病。越来越多的证据表明，细胞凋亡在生理和病理环境中起着至关重要的作用，并且泛素-蛋白酶体系统参与了细胞凋亡的调节。镉是与钴相同的过渡性重金属，据报道可在神经细胞中积累泛素化蛋白。基于这些发现，我们假设钴通过干扰泛素-蛋白酶体途径诱导肺细胞凋亡。为了评估这一点，我们将U-937细胞和人肺泡巨噬细胞（AM）暴露于氯化钴（CoCl 2），并通过DNA片段化分析、4 '，6-二脒基-2'-苯基吲哚二盐酸盐染色和Western印迹分析来检测它们的凋亡。CoCl 2诱导细胞凋亡并积累遍在蛋白。暴露于氯化钴抑制蛋白酶体活性在U-937细胞。钴诱导的细胞凋亡是通过线粒体途径介导的，因为CoCl 2从线粒体释放细胞色素c。这些结果表明，钴诱导的AM凋亡可能是钴诱导肺损伤的机制之一，泛素化蛋白的积累可能参与了这一凋亡过程。
Inhalation of particulate cobalt has been known to induce interstitial lung disease. There is growing evidence that apoptosis plays a crucial role in physiological and pathological settings and that the ubiquitin-proteasome system is involved in the regulation of apoptosis. Cadmium, the same transitional heavy metal as cobalt, has been reported to accumulate ubiquitinated proteins in neuronal cells. On the basis of these findings, we hypothesized that cobalt would induce apoptosis in the lung by disturbance of the ubiquitin-proteasome pathway. To evaluate this, we exposed U-937 cells and human alveolar macrophages (AMs) to cobalt chloride (CoCl2) and examined their apoptosis by DNA fragmentation assay, 4', 6-diamidino-2'-phenylindol dihydrochloride staining, and Western blot analysis. CoCl2 induced apoptosis and accumulated ubiquitinated proteins. Exposure to CoCl2 inhibited proteasome activity in U-937 cells. Cobalt-induced apoptosis was mediated via mitochondrial pathway because CoCl2 released cytochrome c from mitochondria. These results suggest that cobalt-induced apoptosis of AMs may be one of the mechanisms for cobalt-induced lung injury and that the accumulation of ubiquitinated proteins might be involved in this apoptotic process.