PYRROLIDINE DITHIOCARBAMATE AUGMENTS IL-10, INHIBITS TNF-ALPHA, MIP-1-ALPHA, IL-12, AND NITRIC-OXIDE PRODUCTION AND PROTECTS FROM THE LETHAL EFFECT OF ENDOTOXIN

During endotoxemia, immune cells activated by lipopolysaccharide (LPS) produce various inflammatory mediators, including cytokines and nitri c oxide (NO). The genes of several mediators are activated in part by the rapid binding of the transcription factor nuclear factor-kappa B ( NF-kappa B) to its promoter. The induction of this transcription facto r can be blocked by a wide range of antioxidants, including pyrrolidin e dithiocarbamate (PDTC). Here we investigated in mice the effect of t his compound on the plasma tumor necrosis factor-alpha (TNF-alpha), in terferon-gamma (IFN-gamma), interleukin-1 alpha (IL-1 alpha), interleu kin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), macropha ge inflammatory protein-1 alpha (MIP-1 alpha), and nitric oxide (NO) r esponse to intraperitoneal (i.p.) injection of LPS. Pretreatment of an imals with PDTC (10-100 mg/kg) 30 min prior to LPS challenge (4 mg/kg, i.p.) decreased plasma TNF-alpha, IL-12, MIP-1 alpha, and nitrite/nit rate (breakdown products of NO) concentrations, but: enhanced plasma l evels of IL-10. Moreover, pretreatment of mice with PDTC (10-100 mg/kg , i.p.) did not alter LPS-induced (4 mg/kg) production of IL-lcr, IL-6 , and IFN-gamma. Finally, PDTC (100 mg/kg) protected the mice against LPS (100 mg/kg)-induced lethality. These results indicate that blockad e of the NF-kappa B pathway by PDTC has potent anti-inflammatory actio n in systemic inflammatory processes.