ToxSci Advance Access first published online on April 1, 2009
This version published online on April 15, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp054
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Oxidative stress and sodium methyldithiocarbamate-induced modulation of the macrophage response to lipopolysaccharide in vivo
* Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA
Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS
Corresponding author: Stephen B. Pruett, Ph.D. 240 Wise Center Drive, Department of Basic Sciences, College of Veterinary Medicine, P.O. Box 6100, Mississippi State, MS 39762, pruett{at}cvm.msstate.edu, phone: 662-325-1130, fax: 662-325-8884
Received November 15, 2008; revision received March 3, 2009; accepted March 4, 2009
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Abstract |
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Sodium methyldithiocarbamate (SMD) is the third most abundantly used conventional pesticide in the U.S., and hundreds of thousands of persons are exposed to this compound or its major breakdown product, methylisothiocyanate (MITC), at levels greater than recommended by the Environmental Protection Agency. A previous study suggests three mechanisms of action involved to some degree in the inhibition of inflammation and decreased resistance to infection caused by exposure of mice to the compound. One of these mechanisms is oxidative stress. The purpose of the present study was to confirm that this mechanism is involved in the effects of SMD administration to mice on cytokine production by peritoneal macrophages and to further characterize its role in altered cytokine production. Results indicated that SMD significantly decreased the intracellular concentration of reduced glutathione (GSH), suggesting oxidative stress. This was further indicated by the upregulation of genes involved in the "response to oxidative stress" as determined by microarray analysis. These effects were associated with the inhibition of LPS-induced production of several pro-inflammatory cytokines. Experimental depletion of GSH with buthionine sulfoximine (BSO) partially prevented the decrease in LPS-induced IL-6 production caused by SMD and completely prevented the decrease in IL-12. In contrast, BSO plus SMD substantially enhanced the production of IL-10. These results along with results from a previous study are consistent with the hypothesis that SMD causes oxidative stress, which contributes to modulation of cytokine production. However, oxidative stress alone cannot explain the increased IL-10 production caused by SMD.
Key Words: glutathione; Biotransformation and Toxicokinetics, immunotoxicity; Immunotoxicology, inflammation; Immunotoxicology, pesticides; Agents, macrophage; Immunotoxicology.