Effects of Arsenic Trioxide on INF-gamma Gene Expression in MRL/lpr Mice and Human Lupus

Hu, Hongye; Chen, Enjiu; Li, Yongji; Zhu, Xiongzhao; Zhang, Ting; Zhu, Xiaoyu

doi:10.1007/s12011-017-1206-9

Cited by 15 publications

(11 citation statements)

References 36 publications

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“…Our data demonstrated that treatment with ATO decreased the mRNA levels of inflammatory cytokines in the spinal cord and reduced the concentration of IFN-γ in the serum of EAE mice. Consistent with our findings, studies have reported that ATO reduced inflammation in splenocytes of MRL/lpr mice and human lupus peripheral blood mononuclear cells by reducing the expression levels of INF-γ [34]. Collectively, the therapeutic effects of ATO in our study may be partially due to the lower expression levels of proinflammatory cytokines, such as IL-2, IFN-γ, IL-1β, IL-6, and TNF-α.…”

Section: Discussionsupporting

confidence: 92%

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis

Xue

Zhong

et al. 2020

J Neuroinflammation

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Background: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by severe white matter demyelination. Because of its complex pathogenesis, there is no definite cure for MS. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Arsenic trioxide (ATO) is an ancient Chinese medicine used for its therapeutic properties with several autoimmune diseases. It is also used to inhibit acute immune rejection due to its anti-inflammatory and immunosuppressive properties. However, it is unclear whether ATO has a therapeutic effect on EAE, and the underlying mechanisms have not yet been clearly elucidated. In this study, we attempted to assess whether ATO could be used to ameliorate EAE in mice. Methods: ATO (0.5 mg/kg/day) was administered intraperitoneally to EAE mice 10 days post-immunization for 8 days. On day 22 post-immunization, the spinal cord, spleen, and blood were collected to analyze demyelination, inflammation, microglia activation, and the proportion of CD4 + T cells. In vitro, for mechanistic studies, CD4 + T cells were sorted from the spleen of naïve C57BL/6 mice and treated with ATO and then used for an apoptosis assay, JC-1 staining, imaging under a transmission electron microscope, and western blotting. Results: ATO delayed the onset of EAE and alleviated the severity of EAE in mice. Treatment with ATO also attenuated demyelination, alleviated inflammation, reduced microglia activation, and decreased the expression levels of IL-2, IFN-γ, IL-1β, IL-6, and TNF-α in EAE mice. Moreover, the number and proportion of CD4 + T cells in the spinal cord, spleen, and peripheral blood were reduced in ATO-treated EAE mice. Finally, ATO induced CD4 + T cell apoptosis via the mitochondrial pathway both in vitro and in vivo. Additionally, the administration of ATO had no adverse effect on the heart, liver, or kidney function, nor did it induce apoptosis in the spinal cord. Conclusions: Overall, our findings indicated that ATO plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS.

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Section: Discussionsupporting

confidence: 92%

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis

Xue

Zhong

et al. 2020

J Neuroinflammation

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“…Women may convert As to particularly immunosuppressive metabolites, and long-term exposure of men to As during aging may suppress these autoantibodies. These findings are consistent with the association between urinary As and decreased protective antibody response to mumps vaccine [25] and to challenge with purified protein derivative in BCG-vaccinated Bangledesh children [18], and that sex-specific differences may complicate this effect [26], In direct tests arsenic trioxide inhibited interferon-γ synthesis in vitro by lymphocytes from patients with SLE [27] and prolonged survival and decreased anti-nDNA production in lupus-prone mice [28], possibly by inhibiting inflammasome activation [29].…”

Section: Discussionsupporting

confidence: 82%

Elevated autoimmunity in residents living near abandoned uranium mine sites on the Navajo Nation

Erdei

Shuey²,

Pacheco

et al. 2019

Journal of Autoimmunity

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Specific autoantibodies were assessed among residents of the Navajo Nation in New Mexico chronically exposed to metal mixtures from uranium mine wastes and in drinking water supplies. Age and the extent of exposure to legacy waste from 100 abandoned uranium mine and mill sites were associated with antibodies to denatured DNA, previously known to be an early indicator of medication-induced autoimmunity. Surprisingly, autoantibodies to native DNA and/or chromatin were also linked to environmental exposure, specifically uranium consumption through drinking water for both men and women, while urinary arsenic was negatively associated with these autoantibodies in women. These findings suggest that contaminants derived from uranium mine waste enhanced development of autoantibodies in some individuals, while arsenic may be globally immunosuppressive with gender-specific effects. Specific autoantibodies may be a sensitive indicator of immune perturbation by environmental toxicants, an adverse effect not considered in current drinking water standards or regulatory risk assessment evaluations.

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“…Our data demonstrated that treatment with ATO decreased the mRNA level of inflammatory cytokines in the spinal cord and reduced the concentration of IFN-γ in the serum of EAE mice. Consistent with our findings, studies have reported that ATO reduced inflammation in splenocytes of MRL/lpr mice and human lupus peripheral blood mononuclear cells by reducing the expression level of the INF-γ [33]. Collectively, the therapeutic effects of ATO in our study may be partially due to lower expression of proinflammatory cytokines, such as IL-2, IFN-γ, IL-1β, IL-6, and TNF-α.…”

Section: Discussionsupporting

confidence: 92%

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice through inducing apoptosis of CD4+ T cells

Xue

Zhong

et al. 2020

Preprint

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Background: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by severe demyelination of white matter. There is no definite cure for MS owing to its complex pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Arsenic trioxide (ATO) is an ancient Chinese medicine used for its therapeutic properties for several autoimmune diseases. It is also used to inhibit acute immune rejection due to its anti-inflammatory and immunosuppressive properties. However, it is unclear whether ATO has a therapeutic effect on EAE, and the underlying mechanisms have not been clearly elucidated. In this study, we attempted to explore the possibility of using ATO to ameliorate EAE in mice.Methods: ATO (0.5 mg/kg/day) was administered intraperitoneally to EAE mice 10 days post-immunization for 8 days. On day 22 post-immunization, the spinal cord, spleen, and blood were collected to analyze demyelination, inflammation, microglia activation, and proportion of CD4+ T cells. In vitro, for mechanistic studies, CD4+ T cells were sorted from the spleen of naïve C57BL/6 mice and treated with ATO and then used for apoptosis assay, JC-1 staining, transmission electron microscope, and western blotting.Results: ATO delayed the onset of EAE and alleviated the severity of EAE in mice. Treatment with ATO also attenuated demyelination, alleviated inflammation, reduced microglia activation and decreased the expression of IL-2, IFN-γ, IL-1β, IL-6, and TNF-α in EAE mice. Moreover, the number and proportion of CD4+ T cells in the spinal cord, spleen, and peripheral blood were reduced in ATO-treated EAE mice. Finally, ATO induced CD4+ T cells apoptosis through the mitochondrial pathway both in vitro and in vivo. Additionally, the administration of ATO had no adverse effect on the heart, liver, and kidney function and did not induce apoptosis in the spinal cord.Conclusions: Overall, our findings indicated that ATO plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS.

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Effects of Arsenic Trioxide on INF-gamma Gene Expression in MRL/lpr Mice and Human Lupus

Cited by 15 publications

References 36 publications

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis

Elevated autoimmunity in residents living near abandoned uranium mine sites on the Navajo Nation

Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice through inducing apoptosis of CD4+ T cells

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