Oxidative stress and sodium methyldithiocarbamate-induced modulation of the macrophage response to lipopolysaccharide in vivo.

Publisher: Oxford University Press Country of Publication: United States NLM ID: 9805461 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0929 (Electronic) Linking ISSN: 10960929 NLM ISO Abbreviation: Toxicol Sci Subsets: MEDLINE

Publication: 1999- : Cary, NC : Oxford University Press
Original Publication: Orlando, FL : Academic Press, c1998-

Oxidative Stress*; Cytokines/*metabolism ; Lipopolysaccharides/*immunology ; Macrophages, Peritoneal/*immunology ; Pesticides/*toxicity ; Thiocarbamates/*toxicity; Analysis of Variance ; Animals ; Buthionine Sulfoximine/pharmacology ; Female ; Gene Expression Regulation/drug effects ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Macrophages, Peritoneal/drug effects ; Mice ; Oligonucleotide Array Sequence Analysis

Sodium methyldithiocarbamate (SMD) is the third most abundantly used conventional pesticide in the United States, and hundreds of thousands of persons are exposed to this compound or its major breakdown product, methylisothiocyanate, 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 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 lipopolysaccharide (LPS)-induced production of several proinflammatory cytokines. Experimental depletion of GSH with buthionine sulfoximine (BSO) partially prevented the decrease in LPS-induced interleukin (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.

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R01 ES013708 United States ES NIEHS NIH HHS; R01ES013708 United States ES NIEHS NIH HHS

0 (Cytokines)
0 (Lipopolysaccharides)
0 (Pesticides)
0 (Thiocarbamates)
144-54-7 (methyldithiocarbamate)
5072-26-4 (Buthionine Sulfoximine)
GAN16C9B8O (Glutathione)
ULW86O013H (Glutathione Disulfide)

Date Created: 20090403 Date Completed: 20090903 Latest Revision: 20211020

20221213

PMC2721660

10.1093/toxsci/kfp054

19339665