title: Ochratoxin A mediates MAPK activation, modulates IL-2 and TNF-α mRNA expression and induces apoptosis by mitochondria-dependent and mitochondria-independent pathways in human H9 T cells.
abstract: Ochratoxin A (OTA) is a natural fungal secondary metabolite that contaminates food and animal feed. Human exposure and involvement of this mycotoxin in several pathologies have been demonstrated worldwide. We investigated OTA immunotoxicity on H9 cells, a human cutaneous CD4+ T lymphoma cell line. Cells were treated with 0, 1, 5, 10, and 20 µM OTA for up to 24 hr. Western blotting revealed increased phosphorylation of all three major mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun amino-terminal kinase, p38). OTA triggered mitochondrial transmembrane potential loss and caspase-3 activation. The 24-hr OTA treatment caused marked changes in cell morphology and DNA fragmentation, suggesting the occurrence of apoptotic events that involved a mitochondria-dependent pathway. Moreover, OTA triggered significant modulation of survivin, interleukin 2 (IL-2) and tumor necrosis factor α (TNF-α): mRNA expression of survivin and IL-2 were decreased, while TNF-α was increased. OTA also caused caspase-8 activation in a time-dependent manner, which evokes the death receptor pathway activation; we suspect that this occurred via the autocrine pro-apoptotic effect of TNF-α on H9 cells.
authors.affiliation: Laboratory of Physiology and Molecular Genetics, Immunology Unit, Faculty of Sciences, Hassan II Ain Chock University, Morocco.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Darif
authors.forename: Driss
authors.initials: D
authors.lastname: Mountassif
authors.forename: Abdelkarim
authors.initials: A
authors.lastname: Belkebir
authors.forename: Younes
authors.initials: Y
authors.lastname: Zaid
authors.forename: Kaustuv
authors.initials: K
authors.lastname: Basu
authors.forename: Walid
authors.initials: W
authors.lastname: Mourad
authors.forename: Mounia
authors.initials: M
authors.lastname: Oudghiri
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D019898:Autocrine Communication / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009793:Ochratoxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; C508594:IL2 protein, human; D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2; D009793:Ochratoxins; D012333:RNA, Messenger; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha; C025589:ochratoxin A; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8