title: Nodularin induces tumor necrosis factor-alpha and mitogen-activated protein kinases (MAPK) and leads to induction of endoplasmic reticulum stress.
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 factor α (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 1μM) and toxic concentrations (5μM) for 24, 48, and 72h. Transcripts of TNF-α and ER stress marker genes were strongly induced at 1 and 5μM at 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 2.5nM, while HepG2 cells were insensitive up to 10μM due 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, which were analysed here for the first time in detail, may contribute to the hepatotoxic, and tumorigenic action of nodularin.
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland (FHNW), Gründenstrasse 40, CH-4132 Muttenz, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Meili
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland (FHNW), Gründenstrasse 40, CH-4132 Muttenz, Switzerland.
authors.forename: Verena
authors.initials: V
authors.lastname: Christen
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland (FHNW), Gründenstrasse 40, CH-4132 Muttenz, Switzerland; Swiss Federal Institute of Technology Zürich (ETH Zürich), Department of Environmental Systems Science, CH-8092 Zürich, Switzerland. Electronic address: karl.fent@fhnw.ch.
authors.forename: Karl
authors.initials: K
authors.lastname: Fent
mesh_terms: D001427:Bacterial Toxins / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000187:drug effects*; D027361:Organic Anion Transporters / Q000096:biosynthesis; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects*
chemical_list: D001427:Bacterial Toxins; C497249:DDIT3 protein, human; D016209:Interleukin-8; D027361:Organic Anion Transporters; D010456:Peptides, Cyclic; D014409:Tumor Necrosis Factor-alpha; C063998:nodularin; D051742:Transcription Factor CHOP; D020928:Mitogen-Activated Protein Kinases
keywords: ER stress response; MAPK signalling; Nodularin; TNF-α