Article

Inhibition of proteasome activity is involved in cobalt-induced apoptosis of human alveolar macrophages.

First Department of Internal Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Japan.
AJP Lung Cellular and Molecular Physiology (impact factor: 3.66). 11/2002; 283(4):L849-58. DOI:10.1152/ajplung.00422.2001 pp.L849-58
Source: PubMed

ABSTRACT 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 (CoCl(2)) and examined their apoptosis by DNA fragmentation assay, 4',6-diamidino-2'-phenylindol dihydrochloride staining, and Western blot analysis. CoCl(2) induced apoptosis and accumulated ubiquitinated proteins. Exposure to CoCl(2) inhibited proteasome activity in U-937 cells. Cobalt-induced apoptosis was mediated via mitochondrial pathway because CoCl(2) 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.

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Keywords

apoptotic process
 
cobalt
 
cobalt chloride
 
Cobalt-induced apoptosis
 
cobalt-induced lung injury
 
crucial role
 
cytochrome c
 
DNA fragmentation assay
 
human alveolar macrophages
 
induce interstitial lung disease
 
mitochondria
 
mitochondrial pathway
 
neuronal cells
 
particulate cobalt
 
pathological settings
 
transitional heavy metal
 
ubiquitin-proteasome pathway
 
Western blot analysis