Microcystin-LR induces endoplasmatic reticulum stress and leads to induction of NFκB, interferon-alpha, and tumor necrosis factor-alpha.
Environ Sci Technol
; 47(7): 3378-85, 2013 Apr 02.
Article
em En
| MEDLINE
| ID: mdl-23431999
ABSTRACT
Microcystins (MCs) are hepatotoxins produced by cyanobacteria responsible for toxicity in humans and animals. Here, we investigate unexplored molecular pathways by which microcystin-LR (MC-LR) acts on hepatocytes to elucidate unknown modes of action. We focus on the endoplasmatic reticulum (ER) stress response or unfolded protein response (UPR), and on mechanisms that may contribute to the tumor-promoting effect of MCs in animals, including the activation of NFκB, the expression of interferon alpha (IFN-α) and the induction of interferon stimulated genes (ISGs), as well as the expression of tumor necrosis factor alpha (TNF-α). To this end, we exposed human hepatoma cells (Huh7) to 0.5 µM (nontoxic concentration), 5 µM (EC50 concentration), 25 µM and 50 µM (cytotoxic concentrations) MC-LR for 6, 24, 48, and 72 h. The expression of phosphatase 2A (PP2A) mRNA and protein was induced at 5 µM MC-LR. Phosphorylated P-CREB, a transcription factor for PP2A, leads to elevated expression of PP2A. Furthermore, all of the three ER stress pathways, the UPR and the endoplasmic reticulum-associated degradation were activated after exposure to 5, 25, and 50 µM MC-LR. Additionally, the expression of NFκB, IFN-α, and several INF-α-stimulated genes was strongly activated. The proinflammatory cytokine TNF-α was also induced. Our data demonstrate that MC-LR induces all ER stress response pathways. Consequently NFκB is activated, which in turn induces the expression of IFN-α and TNF-α. All of these activated pathways, which are analyzed here for the first time in detail, may contribute to the hepatotoxic, inflammatory, and tumorigenic action of MC-LR.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
NF-kappa B
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Fator de Necrose Tumoral alfa
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Interferon-alfa
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Microcistinas
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Estresse do Retículo Endoplasmático
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Environ Sci Technol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Suíça