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To investigate the role of interferon regulatory factor-1 (IRF-1) in the development of lupus nephritis, IRF-1 -/-genotype mice were bred onto the MRL/lpJfas lpr (MRL/lpr) background. We examined kidney mesangial cell function and disease progression. Endpoints evaluated included inflammatory mediators, autoantibody production, immune complex deposition, renal pathology, T cell subset analysis, and duration of survival. Mesangial cells cultured from IRF-1 -/-mice produced significantly lower levels of nitric oxide and IL-12 but not TNF-a when stimulated with LPS + IFN-c. IRF-1 -/-mice showed less aggravated dermatitis compared to the wild-type mice. Anti-doublestranded DNA production and proteinuria were significantly decreased in IRF-1 -/-mice compared to IRF-1 +/+ mice. IgG and C3 deposition as well as glomerulonephritis were decreased in IRF-1 -/-mice at 26 wk of age compared to the IRF-1 +/+ mice. Splenic CD4 -CD8 -CD44 + T cells were decreased while CD4 + CD25 + T cells were increased in the IRF-1 -/-mice when compared to IRF-1 +/+ mice. Survival rates (ED 50 ) were 22 wk for IRF-1 +/+ mice and 45 wk for IRF-1 -/-mice. These findings suggest an important role of IRF-1 in mediating renal disease in MRL/lpr mice. IntroductionThe etiology of systemic lupus erythematosus remains an enigma although genetic factors influenced by environmental agents appear to trigger the disease. Clearly, B cells, T cells, and macrophages play important roles in the development of lupus pathology [1][2][3].Chronic expression of Th1 cytokines secreted by Th cells is particularly harmful due to their influence on the initiation and promotion of tissue destruction [4,5]. Cytokines, including IFN-c, promote inflammation and provide a positive amplification loop responsible for escalating autoimmune kidney damage [6].MRL/lpr mice develop glomerulonephritis and vasculitis at an early age (4-5 months) [7]. Renal disease is characterized by the early influx of activated T cells and macrophages into the kidney. Activated T cells secrete IFN-c, which induces macrophages to express CSF-1, IL-1b, and TNF-a. Macrophages accumulate in the kidney during inflammation and generate IFN-a, TNF-a, and reactive oxygen species. Locally produced chemokines, particularly monocyte chemoattractant protein (MCP)-1, are also instrumental in attracting and maintaining cellular influx [8] -12 [20]. In the IRF-1 -/-NOD mouse, insulitis and diabetes were decreased accompanied by an increased survival [21]. Additional studies have suggested a role of IRF-1 and IFN-regulated genes in mediating human lupus [22][23][24]. Based on the knowledge that IRF-1 modulates inflammatory mediator production, we sought to determine whether IRF-1 gene deletion alters the severity of lupus nephritis in MRL/lpr mice. Results IRF-1 MRL/lpr mouse phenotypeTo determine the role of IRF-1 in autoimmune disease, IRF-1-knockout mice were backcrossed for eight generations to the MRL/lpr mice. After eight backcrosses, the littermates were intercrossed to yield cohorts for these studies....

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The role of oxidative stress in immune cell toxicity caused by the pesticides lindane, malathion and permethrin was investigated in thymic cells from C57BL/6 mice. Thymocytes treated with any of these pesticides (concentrations ranging between 50-150 microM) were found to generate both superoxide ((*)O(2) (-)) and H(2)O(2). The production of (*)O(2) (-) was detected with hydroethidine-ethidium bromide assay. H(2)O(2) production was monitored with a flow cytometric fluorescent (DCFH-DA) assay. All three pesticides stimulated (*)O(2) (-) release after 5 min exposure. Lindane and permethrin, but not malathion, continued to have significant (p < or = 0.05) effects on (*)O(2) (-) generation following 15 min of exposure. The lindane + malathion mixture was found to cause more-than-additive increase in (*)O(2) (-) production compared to individual pesticide treatments (at both 5 and 15 min). However, the effect of the lindane + permethrin mixture was not significantly different than individual components of this mixture. The effects of these pesticides on levels of antioxidant enzymes were also investigated, and only mixtures were found to have significant (p < or = 0.05) effects. Thus, lindane + malathion and lindane + permethrin mixtures increased total superoxide dismutase (SOD) specific activity, had no effect on catalase levels and inhibited GSH-peroxidase and GSH-reductase specific activities. Although the results of these studies do not explain the mechanism of action of these pesticides on the generation of (*)O(2) (-) and H(2)O(2), it is worthy of note that mixtures of these chemicals have oxidative responses greater than those of single chemicals.