Exposure of experimental animals or cultured cells to arsenic induces oxidative stress, but, to date, no examination of this phenomenon in humans has been reported. In this study we conducted a cross-sectional study in Wuyuan, Inner Mongolia, China, to explore the relationship between chronic arsenic exposure from drinking water and oxidative stress in humans. Thirty-three inhabitants who had been drinking tube-well water with high concentrations of inorganic arsenic (mean value = 0.41 mg/L) for about 18 years constituted the high-exposure group, and 10 residents who lived nearby but were exposed to much lower concentrations of arsenic in their drinking water (mean value = 0.02 mg/L) were selected as the low-exposure comparison group. Results of the present study indicated that although the activity for superoxide dismutase (SOD) in blood did not differ significantly between the two groups, the mean serum level of lipid peroxides (LPO) was significantly higher among the high-exposed compared with the low-exposed group. Elevated serum LPO concentrations were correlated with blood levels of inorganic arsenic and its methylated metabolites. In addition, they showed an inverse correlation with nonprotein sulfhydryl (NPSH) levels in whole blood. The subjects in the high-arsenic-exposure group had mean blood NPSH levels 57.6% lower than those in the low-exposure group. Blood NPSH levels were inversely correlated with the concentrations of inorganic arsenic and its methylated metabolites in blood and with the ratio of monomethylarsenic to inorganic arsenic. These results provide evidence that chronic exposure to arsenic from drinking water in humans results in induction of oxidative stress, as indicated by the reduction in NPSH and the increase in LPO. Some possible mechanisms for the arsenic-induced oxidative stress are discussed.

Objective Interleukin‐18 (IL‐18) is a proinflammatory cytokine that is involved in immunologically mediated tissue damage, but its bioactivity is regulated in vivo by its soluble decoy receptor, IL‐18 binding protein (IL‐18BP). This study was undertaken to determine levels of IL‐18 and IL‐18 binding inhibition in the blood of patients with adult‐onset Still's disease (ASD). Methods Serum concentrations of IL‐18 in ASD patients were compared by enzyme‐linked immunosorbent assay (ELISA) with those in patients with other systemic rheumatic diseases and healthy controls. The biologically active mature protein of IL‐18 was detected by Western blot analysis with anti–IL‐18 antibody and its induction of interferon‐γ (IFNγ) secretion from IL‐18–responding human myelomonocytic KG‐1 cells. The inhibitory activity on IL‐18 binding to its receptor was determined by 125I–IL‐18 binding inhibition assay using the Chinese hamster ovary cell line transfected with a murine IL‐18 receptor (CHO‐K1/mIL‐18R). Results Concentrations of serum IL‐18 were extremely elevated in patients with active ASD compared with those in patients with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis, Sjögren's syndrome, or healthy individuals. Levels of IL‐18 were found to correlate with serum ferritin values and disease severity in ASD. Western blot analysis revealed that serum samples from patients with active ASD contained an 18‐kd polypeptide of IL‐18, corresponding in size to the mature form. Accordingly, the samples were able to induce IFNγ secretion from KG‐1 cells, which was largely abolished by neutralizing anti–IL‐18 antibody. However, the level of IL‐18 bioactivity was more than 10‐fold weaker than the concentration of IL‐18 protein measured by ELISA. Serum samples from patients with active ASD showed an inhibitory effect on the binding of 125I–IL‐18 to CHO‐K1/mIL‐18R cells, and this activity was associated with elevation of IL‐18. Conclusion These data indicate that systemic overproduction of IL‐18 may be closely related to the pathogenesis of ASD, despite the restriction on its inflammatory activity by IL‐18 binding inhibitors such as IL‐18BP. The disease activity appears to be determined on the basis of the relative levels of IL‐18 and its specific inhibitors.

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IL-18 is a recently described cytokine that shares biological activities with IL-12 in driving the development of Th1-type T cells. As dendritic cells (DC) are very potent inducers of T cell proliferation and differentiation we wondered whether they utilize IL-18 as a factor driving Th1 development. We demonstrate by Northern blot and reverse transcription-PCR that various subtypes of human and murine DC as well as the DC-line XS contain IL-18 mRNA. When supernatants of either enriched Langerhans cells (LC) or bone marrow-derived DC were analyzed for production of IL-18 protein, IL-18 production was detected in an IL-18-specific ELISA. To assess whether the IL-18 protein released by DC is functional, we performed a sensitive bioassay using the IL-18-dependent stimulation of concanavalin A-stimulated T cells. Both, supernatants from bone marrow-derived DC and enriched LC induced IFN-gamma production in the T cells. This production was partially inhibitable by addition of anti-IL-18 antiserum. In a TCR-transgenic mouse system we further demonstrate that DC-derived IL-18 potentiates IL-12-dependent Th1 development. Using DC derived from IL-12 knockout animals, we show that DC-derived IL-18 by itself is not capable of inducing Th1 cell differentiation. Together the data demonstrate that subtypes of DC are able to release functional IL-18 that is able to induce IFN-gamma production and Th1 differentiation in primed T cells.

IL-18 is a recently described cytokine that shares biological activities with IL-12 in driving the development of Th1-type T cells. As dendritic cells (DC) are very potent inducers of T cell proliferation and differentiation we wondered whether they utilize IL-18 as a factor driving Th1 development. We demonstrate by Northern blot and reverse transcription-PCR that various subtypes of human and murine DC as well as the DC-line XS contain IL-18 mRNA. When supernatants of either enriched Langerhans cells (LC) or bone marrow-derived DC were analyzed for production of IL-18 protein, IL-18 production was detected in an IL-18-specific ELISA. To assess whether the IL-18 protein released by DC is functional, we performed a sensitive bioassay using the IL-18-dependent stimulation of concanavalin A-stimulated T cells. Both, supernatants from bone marrow-derived DC and enriched LC induced IFN-+ production in the T cells. This production was partially inhibitable by addition of anti-IL-18 antiserum. In a TCR-transgenic mouse system we further demonstrate that DC-derived IL-18 potentiates IL-12-dependent Th1 development. Using DC derived from IL-12 knockout animals, we show that DC-derived IL-18 by itself is not capable of inducing Th1 cell differentiation. Together the data demonstrate that subtypes of DC are able to release functional IL-18 that is able to induce IFN-+ production and Th1 differentiation in primed T cells.