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Toxicological Sciences 55, 206-214 (2000)
Copyright © 2000 by the Society of Toxicology

Systems Toxicology

Diethyldithiocarbamate Enhances Production of Nitric Oxide and TNF-{alpha} by Lipopolysaccharide-Stimulated Rat Kupffer Cells

Hironobu Ishiyama1, Niel C. Hoglen2 and I. Glenn Sipes

Department of Pharmacology and Toxicology, Center for Toxicology, The University of Arizona, Tucson, Arizona 85721

Previous studies have shown that large doses of diethyldithiocarbamate (DDC) cause liver injury in rats and the pathogenesis of this injury involves, in part, release of superoxide anion by Kupffer cells. The purpose of this study was to evaluate if DDC was able to stimulate other potentially toxic mediators such as nitric oxide (NO) and tumor necrosis factor-{alpha} (TNF-{alpha}) using isolated rat Kupffer cells. DDC alone did not stimulate the release of NO and TNF-{alpha} by Kupffer cells. Interestingly, when Kupffer cells were stimulated by lipopolysaccharide (LPS), DDC (0–30 µM) enhanced the production of both NO and TNF-{alpha} in a concentration-dependent manner. Therefore, we further studied how DDC modulated the response of Kupffer cells to LPS. Immunocytochemical studies revealed that DDC increased the amount of inducible NO synthase and TNF-{alpha} protein in Kupffer cells after their exposure to LPS. The enhanced effects of DDC on the release of NO and TNF-{alpha} from Kupffer cells was inhibited by N-acetyl-L-cysteine (an inhibitor of transcription factor NF-{kappa}B activation). By using a specific antibody for NF-{kappa}Bp65, it was found that DDC enhanced the LPS-activated nuclear translocation of NF-{kappa}B. There was no evidence of intracellular oxidative stress following either LPS alone or DDC + LPS exposure. The stimulatory effect of DDC on both NO and TNF-{alpha} release was inhibited by H-7 (an inhibitor of protein kinase C) but not H-8 (an inhibitor of cAMP-dependent protein kinase). These findings demonstrate that DDC enhances the production of NO and TNF-{alpha} by LPS-stimulated Kupffer cells and suggest that protein kinase C plays a critical role in mediating these effects of DDC.

Key Words: diethyldithiocarbamate (DDC); rat Kupffer cells; tumor necrosis factor-{alpha} (TNF-{alpha}); nitric oxide; oxidative stress; NF-{kappa}B; protein kinase C.


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