Nodularin induces tumor necrosis factor-alpha and mitogen-activated protein kinases (MAPK) and leads to induction of endoplasmic reticulum stress
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Publication date
01.06.2016
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01A - Journal article
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Toxicology and Applied Pharmacology
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300
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Pages / Duration
25-33
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Elsevier
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Abstract
Nodularin is produced by the cyanobacterium Nodularia spumigena. It is of concern due to hepatotoxicity in
humans and animals. Here we investigated unexplored molecular mechanisms by transcription analysis in
human liver cells, focusing on induction of pro-inflammatory cytokines, the tumor necrosis factorα (TNF-α), endoplasmic
reticulum (ER) stress and components of the activator protein-1 complex in human hepatoma cells
(Huh7) exposed to non-cytotoxic (0.1 and 1 μM) and toxic concentrations (5 μM) for 24, 48, and 72 h. Transcripts
of TNF-α and ER stressmarker geneswere strongly induced at 1 and 5 μMat all time-points. TNF-α led to induction
of mitogen-activated protein kinases (MAPK), as demonstrated by induction of CJUN and CFOS, which form
the AP-1 complex. Human primary liver cells reacted more sensitive than Huh7 cells. They showed higher cytotoxicity
and induction of TNF-α and ER stress at 2.5 nM, while HepG2 cells were insensitive up to 10 μMdue to
low expression of organic anion transporting polypeptides. Furthermore, nodularin led to induction of TNF-α
protein, and CCAAT/enhancer-binding protein-homologous (CHOP) protein. Our data indicate that nodularin induces
inflammation and ER stress and leads to activation of MAPK in liver cells. All of these activated pathways,
whichwere analysed here for the first time in detail,may contribute to the hepatotoxic, and tumorigenic action of
nodularin.
Keywords
Nodularin, ER stress response, TNF-α, MAPK signalling
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1096-0333
0041-008X
0041-008X
Language
English
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Yes
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Published
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Citation
Meili, N., Christen, V., & Fent, K. (2016). Nodularin induces tumor necrosis factor-alpha and mitogen-activated protein kinases (MAPK) and leads to induction of endoplasmic reticulum stress. Toxicology and Applied Pharmacology, 300, 25–33. https://doi.org/10.1016/j.taap.2016.03.014