Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes

Morzadec, Claudie; Macoch, Mélinda; Robineau, Marc; Sparfel, Lydie; Fardel, Olivier; Vernhet, Laurent

doi:10.1016/j.taap.2012.05.004

Cited by 23 publications

(20 citation statements)

References 31 publications

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“…Many of the current findings rely on the use of peripheral blood and biomarkers to infer the cells and organs that are affected by arsenic [9], [17], [25], [26]. In addition, there have been in vitro studies with arsenite (As +3 ) at micromolar concentrations in human leukocytes that demonstrate altered immune effects possibly by affecting T cells and macrophage/dendritic cells [27], [28], [29]. Also, it has been observed that micromolar concentrations of As +3 induce necrosis of human CD34+ bone marrow cells [30].…”

Section: Discussionmentioning

confidence: 99%

Arsenite Selectively Inhibits Mouse Bone Marrow Lymphoid Progenitor Cell Development In Vivo and In Vitro and Suppresses Humoral Immunity In Vivo

et al. 2014

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It is known that exposure to As+3 via drinking water causes a disruption of the immune system and significantly compromises the immune response to infection. The purpose of these studies was to assess the effects of As+3 on bone marrow progenitor cell colony formation and the humoral immune response to a T-dependent antigen response (TDAR) in vivo. In a 30 day drinking water study, mice were exposed to 19, 75, or 300 ppb As+3. There was a decrease in bone marrow cell recovery, but not spleen cell recovery at 300 ppb As+3. In the bone marrow, As+3 altered neither the expression of CD34+ and CD38+ cells, markers of early hematopoietic stem cells, nor CD45−/CD105+, markers of mesenchymal stem cells. Spleen cell surface marker CD45 expression on B cells (CD19+), T cells (CD3+), T helper cells (CD4+) and cytotoxic T cells (CD8+), natural killer (NK+), and macrophages (Mac 1+) were not altered by the 30 day in vivo As+3 exposure. Functional assays of CFU-B colony formation showed significant selective suppression (p<0.05) by 300 ppb As+3 exposure, whereas CFU-GM formation was not altered. The TDAR of the spleen cells was significantly suppressed at 75 and 300 ppb As+3. In vitro studies of the bone marrow revealed a selective suppression of CFU-B by 50 nM As+3 in the absence of apparent cytotoxicity. Monomethylarsonous acid (MMA+3) demonstrated a dose-dependent and selective suppression of CFU-B beginning at 5 nM (p<0.05). MMA+3 suppressed CFU-GM formation at 500 nM, a concentration that proved to be nonspecifically cytotoxic. As+5 did not suppress CFU-B and/or CFU-GM in vitro at concentrations up to 500 nM. Collectively, these results demonstrate that As+3 and likely its metabolite (MMA+3) target lymphoid progenitor cells in mouse bone marrow and mature B and T cell activity in the spleen.

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Section: Discussionmentioning

confidence: 99%

Arsenite Selectively Inhibits Mouse Bone Marrow Lymphoid Progenitor Cell Development In Vivo and In Vitro and Suppresses Humoral Immunity In Vivo

et al. 2014

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“…8B). We previously reported that cell pre-treatment with As(III) reduces the aCD3/aCD28-induced expression of IL-2, IFN-J, and IL-17 [19,20]. As(III)-dependent activation of Nrf2 could therefore mediate these inhibitory effects.…”

Section: Extinction Of Nrf2 Does Not Modify the Expression Of Genes Cmentioning

confidence: 97%

“…Th cells from Nrf2 knockout mice secrete higher amounts of IFN-J and TNF-D than20 their control counterparts from wild-type mice. The results of this study do not support a role for Nrf2 in the regulation of cytokine synthesis in human Th cells, since genetic invalidation of Nrf2 expression does not up-regulate mRNA levels of IL2, IFNG, TNF, and IL17 genes in Th cells activated in the absence or presence of As(III).…”

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confidence: 90%

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Nrf2 expression and activity in human T lymphocytes: stimulation by T cell receptor activation and priming by inorganic arsenic and tert-butylhydroquinone

Morzadec

Macoch

Sparfel

et al. 2014

Free Radical Biology and Medicine

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The transcription factor nuclear factor-erythroid 2-related-2 (Nrf2) controls cellular redox homeostasis and displays immunomodulatory properties. Nrf2 alters cytokine expression in murine T cells, but its effects in human T lymphocytes are unknown. This study investigated the expression and activity of Nrf2 in human activated CD4(+) T helper lymphocytes (Th cells) that mediate the adaptive immune response. Th cells were isolated from peripheral blood mononuclear cells and activated with antibodies against CD3 and CD28, mimicking physiologic Th cell stimulation by dendritic cells. Nrf2 is hardly detectable in unstimulated Th cells. Activation of Th cells rapidly and strongly increases the levels of Nrf2 protein by increasing NRF2 gene transcription. Th cell activation also enhances mRNA and protein levels of Nrf2 target genes encoding antioxidant enzymes. Blocking Nrf2 expression using chemical inhibitors or siRNAs prevents these gene inductions. Pretreatment with inorganic arsenic, a Nrf2 inducer that does not alter NRF2 gene expression, increases protein level and transcriptional activity of Nrf2 induced by Th cell stimulation. Inorganic arsenic enhances nuclear translocation of Nrf2, its interaction with the coactivator protein p300, and its DNA binding activity. Inhibition of Nrf2 expression abrogates the effects of inorganic arsenic on mRNA levels of antioxidant genes, but does not alter the expression of IL-2, TNF-α, interferon-γ, or IL-17 in Th cells activated in the absence or presence of the metalloid. In conclusion, this study demonstrates for the first time that stimulation of human Th cells increases transcription of the NRF2 gene and activity of the Nrf2 protein. However, modulation of Nrf2 levels does not modify the secretion of inflammatory cytokines from these T lymphocytes.

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“…As markedly suppressed lymphocyte secretion and/or mRNA levels of IFN-γ, IL-4 and IL-10 in different in vitro models [114,116,117]. As III also significantly impaired differentiation of human Th17 cells by repressing their expression and release of IL-17 and decreasing expression of RORγt, which regulates IL-17, through inactivation of JNK/c-Jun pathway [120]. As III further impaired Th17 cells by disrupting functions of DC, which regulate Th17 cell differentiation, via i) blocking DC differentiation through induced necrosis; ii) decreasing DC endocytotic activity; iii) repressing secretion of IL-12p70 and IL-23, two major regulators of Th17 activities, by activated DC; and iv) reducing ability of activated DC to stimulate IFN-γ and IL-17 release from Th17 cells [121].…”

Section: In Vitro Studiesmentioning

confidence: 99%

Arsenic immunotoxicity: a review

2013

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Exposure to arsenic (As) is a global public health problem because of its association with various cancers and numerous other pathological effects, and millions of people worldwide are exposed to As on a regular basis. Increasing lines of evidence indicate that As may adversely affect the immune system, but its specific effects on immune function are poorly understood. Therefore, we conducted a literature search of non-cancer immune-related effects associated with As exposure and summarized the known immunotoxicological effects of As in humans, animals and in vitro models. Overall, the data show that chronic exposure to As has the potential to impair vital immune responses which could lead to increased risk of infections and chronic diseases, including various cancers. Although animal and in vitro models provide some insight into potential mechanisms of the As-related immunotoxicity observed in human populations, further investigation, particularly in humans, is needed to better understand the relationship between As exposure and the development of disease.

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Inorganic arsenic represses interleukin-17A expression in human activated Th17 lymphocytes

Cited by 23 publications

References 31 publications

Arsenite Selectively Inhibits Mouse Bone Marrow Lymphoid Progenitor Cell Development In Vivo and In Vitro and Suppresses Humoral Immunity In Vivo

Arsenite Selectively Inhibits Mouse Bone Marrow Lymphoid Progenitor Cell Development In Vivo and In Vitro and Suppresses Humoral Immunity In Vivo

Nrf2 expression and activity in human T lymphocytes: stimulation by T cell receptor activation and priming by inorganic arsenic and tert-butylhydroquinone

Arsenic immunotoxicity: a review

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