p38 mitogen-activated protein kinase mediates IL-8 induction by the ribotoxin deoxynivalenol in human monocytes
- Department of Food Science and Human Nutrition, Michigan State University, 234 G.M. Trout Building, East Lansing, MI 48824-1224 (United States)
- Center for Integrative Toxicology, Michigan State University, 234 G.M. Trout Building, Michigan State University, East Lansing, MI 48824-1224 (United States)
- Department of Food Science and Human Nutrition, Michigan State University, 234 G.M. Trout Building, East Lansing, MI 48824-1224 (United States) and Center for Integrative Toxicology, Michigan State University, 234 G.M. Trout Building, Michigan State University, East Lansing, MI 48824-1224 (United States) and Department of Microbiology and Molecular Genetics, Michigan State University, 234 G.M. Trout Building, East Lansing, MI 48824-1224 (United States)
The effects of the ribotoxic trichothecene deoxynivalenol (DON) on mitogen-activated protein kinase (MAPK)-mediated IL-8 expression were investigated in cloned human monocytes and peripheral blood mononuclear cells (PBMC). DON (250 to 1000 ng/ml) induced both IL-8 mRNA and IL-8 heteronuclear RNA (hnRNA), an indicator of IL-8 transcription, in the human U937 monocytic cell line in a concentration-dependent manner. Expression of IL-8 hnRNA, mRNA and protein correlated with p38 phosphorylation and was completely abrogated by the p38 MAPK inhibitor SB203580. DON at 500 ng/ml similarly induced p38-dependent IL-8 protein and mRNA expression in PBMC cultures from healthy volunteers. Significantly increased IL-6 and IL-1{beta} intracellular protein and mRNA expression was also observed in PBMC treated with DON (500 ng/ml) which were also partially p38-dependent. Flow cytometry of PBMC revealed that DON-induced p38 phosphorylation varied among individuals relative to both threshold toxin concentrations (25-100 ng/ml) and relative increases in percentages of phospho-p38{sup +} cells. DON-induced p38 activation occurred exclusively in the CD14{sup +} monocyte population. DON was devoid of agonist activity for human Toll-like receptors 2, 3, 4, 5, 7, 8 and 9. However, two other ribotoxins, emetine and anisomycin, induced p38 phosphorylation in PBMC similarly to DON. Taken together, these data suggest that (1) p38 activation was required for induction of IL-8 and proinflammatory gene expression in the monocyte and (2) DON induced p38 activation in human monocytes via the ribotoxic stress response.
- OSTI ID:
- 20850346
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 213; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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