Inhibition of proteasome activity is involved in cobalt-induced apoptosis of human alveolar macrophages.
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.
Araya
Jun
J
First Department of Internal Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Japan.
Maruyama
Muneharu
M
Inoue
Akira
A
Fujita
Tadashi
T
Kawahara
Junko
J
Sassa
Kazuhiko
K
Hayashi
Ryuji
R
Kawagishi
Yukio
Y
Yamashita
Naohiro
N
Sugiyama
Eiji
E
Kobayashi
Masashi
M
D016587:Antimutagenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003035:Cobalt / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D016676:Macrophages, Alveolar / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D008928:Mitochondria / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D017382:Reactive Oxygen Species / Q000378:metabolism; D020298:U937 Cells; D025801:Ubiquitin / Q000378:metabolism
D016587:Antimutagenic Agents; D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D025801:Ubiquitin; D003035:Cobalt; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C018021:cobaltous chloride