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ToxSci Advance Access originally published online on June 23, 2005
Toxicological Sciences 2005 87(1):113-122; doi:10.1093/toxsci/kfi234
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Induction of Competing Apoptotic and Survival Signaling Pathways in the Macrophage by the Ribotoxic Trichothecene Deoxynivalenol

Hui-Ren Zhou*,{dagger}, Zahidul Islam*,{ddagger} and James J. Pestka*,{dagger},{ddagger},1

Departments of * Microbiology and Molecular Genetics, {dagger} Food Science and Human Nutrition, and {ddagger} Center for Integrative Toxicology, Michigan State University, East Lansing Michigan 48824-1224

Received March 7, 2005; accepted June 7, 2005

Deoxynivalenol (DON) and other ribotoxic trichothecenes cause immune stimulation and suppression in leukocytes by upregulating gene expression and apoptosis, respectively. The purpose of this study was to test the hypothesis that MAPKs mediate both apoptosis and survival in DON-exposed macrophages. At concentrations which partially inhibit translation, DON induced phosphorylation of p38 and ERK 1/2 mitogen activated protein kinases within 15 min in RAW 264.7 macrophages and these effects lasted up to 3 h. DON-exposed cells exhibited marked caspase 3-dependent DNA fragmentation after 6 h which was suppressed and attenuated by the p38 inhibitor SB203580 and ERK inhibitor PD98059, respectively. DON readily induced the phosphorylation and activity of p53 and this was inhibitable by SB203580. DON exposure evoked BAX translocation to mitochondria and corresponding cytochrome C release but did not alter mitochondrial membrane potential. The p53 inhibitor PFT{alpha} reduced both DON-induced phosphorylation of p53 and p53 binding activity. Moreover, both PFT{alpha} and p53 siRNA transfection suppressed DON-induced caspase-3 activity and subsequent DNA fragmentation. Concurrent with p53 activation, DON activated two anti-apoptotic survival pathways as evidenced by both ERK-dependent p90 Rsk and AKT activation. Taken together, the results indicate that DON initiates competing apoptotic (p38/p53/Bax/Mitochondria/Caspase-3) and survival (ERK/AKT/p90Rsk/Bad) pathways in the macrophage.

Key Words: deoxynivalenol; trichothecene; apoptosis; macrophages; ribotoxic.


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