Induction of apoptosis and cytokine production in the Jurkat human T cells by deoxynivalenol: role of mitogen-activated protein kinases and comparison to other 8-ketotrichothecenes.
The Jurkat T-cell line was used to study potential impact of deoxynivalenol (DON) and related 8-ketotrichothecenes on human immune function. DON (250-1000 ng/ml) readily induced caspase-3 and apoptosis in Jurkat cells. DON (62.5-500 ng/ml) also significantly upregulated IL-2 and IL-8 production following prestimulation with phorbol myristate acetate and ionomycin. DON markedly induced phosphorylation of p38, JNK 1/2, and ERK2. SB203580, a specific inhibitor of p38, reduced DON-induced apoptosis. The MEK1 inhibitor PD98059 which blocks ERK activation had only a small inhibitory effect on DON-induced apoptosis while the JNK inhibitor SP600125 was without effect. Inhibition of p38 attenuated DON-induced upregulation of IL-2 while all three MAPK inhibitors suppressed IL-8 upregulation. When effects of DON were compared to other 8-ketotrichothecenes, the concentrations of DON, 3-acetyl deoxynivalenol (3-ADON), 15-acetyl deoxynivalenol (15-ADON), nivalenol (NIV) and fusarenon X (FX) causing 50% apoptosis were 0.6, 0.5, 0.5, 0.5 and 7.5 microg/ml, respectively. Relative to IL-2 upregulation, FX was suppressive whereas 3-ADON, 15-ADON and NIV had no effect at concentrations of 62.5-500 ng/ml. In contrast, 15-ADON at 62.5-500 ng/ml and 3-ADON at 625-5000 ng/ml upregulated IL-8 production but FX and NIV had no effect. Taken together, these data suggest that DON's effects on apoptosis and cytokine production were differentially regulated by MAPKs. Although DON shared its capacity to induce apoptosis and potentiate IL-8 production with other 8-ketotrichothecenes, it appeared to be unique in its capacity to upregulate IL-2.
Pestka
James J
JJ
Department of Food Science and Human Nutrition, 234 G.M. Trout FSHN Building, Michigan State University, East Lansing, MI 48824-1224, USA. pestka@msu.edu
Uzarski
Rebecca L
RL
Islam
Zahidul
Z
D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000922:Immunotoxins / Q000633:toxicity*; D019169:Jurkat Cells; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology*; D009183:Mycotoxins / Q000633:toxicity*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D014255:Trichothecenes / Q000276:immunology* / Q000633:toxicity
D000873:Anthracenes; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D000922:Immunotoxins; D009183:Mycotoxins; D011725:Pyridines; D014255:Trichothecenes; C432165:pyrazolanthrone; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C007262:deoxynivalenol; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one