Sodium arsenite retards proliferation of PHA-activated T cells by delaying the production and secretion of IL-2

Galicia, Georgina; Leyva, Rosario; Tenorio, Eda Patricia; Ostrosky‐Wegman, Patricia; Saavedra, Rafael

doi:10.1016/s1567-5769(03)00049-3

Cited by 47 publications

(36 citation statements)

References 41 publications

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“…iAs was first demonstrated to markedly alter physiology of lymphocytes, not only in vitro and in rodents, but also in chronically exposed humans (8,9). In addition, we and others have recently demonstrated that monocytes/macrophages constituted critical targets for iAs (10 -13).…”

Section: Norganic Arsenic (Ias)mentioning

confidence: 93%

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Lemarié

Bourdonnay

Morzadec

et al. 2008

The Journal of Immunology

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Inorganic arsenic is an immunotoxic environmental contaminant to which millions of humans are chronically exposed. We recently demonstrated that human primary macrophages constituted a critical target for arsenic trioxide (As2O3), an inorganic trivalent form. To specify the effects of arsenic on macrophage phenotype, we investigated in the present study whether As2O3 could regulate the activity of NADPH oxidase, a major superoxide-generating enzymatic system in human phagocytes. Our results show that superoxide levels were significantly increased in a time-dependent manner in blood monocyte-derived macrophages treated with 1 μM As2O3 for 72 h. Concomitantly, As2O3 induced phosphorylation and membrane translocation of the NADPH oxidase subunit p47phox and it also increased translocation of Rac1 and p67phox. Apocynin, a selective inhibitor of NADPH oxidases, prevented both p47phox translocation and superoxide production. NADPH oxidase activation was preceded by phosphorylation of p38-kinase in As2O3-treated macrophages. The p38-kinase inhibitor SB-203580 prevented phosphorylation and translocation of p47phox and subsequent superoxide production. Pretreatment of macrophages with the Rho-kinase inhibitor Y-27632 was found to mimic inhibitory effects of SB-203580 and to prevent As2O3-induced phosphorylation of p38 kinase. Treatment with As2O3 also resulted in an increased secretion of the proinflammatory chemokine CCL18 that was fully inhibited by both apocynin and SB-203580. Taken together, our results demonstrate that As2O3 induced a marked activation of NADPH oxidase in human macrophages, likely through stimulation of a Rho-kinase/p38-kinase pathway, and which may contribute to some of the deleterious effects of inorganic arsenic on macrophage phenotype.

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Section: Norganic Arsenic (Ias)mentioning

confidence: 93%

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Lemarié

Bourdonnay

Morzadec

et al. 2008

The Journal of Immunology

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“…In these individuals, increased urine arsenic levels were associated with reduced CD4 lymphocyte population, proliferative response to PHA, and IL-2 secretion. Moreover, low micromolar concentrations of arsenite, an inorganic trivalent arsenical compound, delays in vitro proliferation of activated human T lymphocytes by reducing production and secretion of IL-2 (8). Alterations of lymphocyte functions have also been observed in animal models.…”

Section: Norganic Arsenic (Ias)mentioning

confidence: 99%

Human Macrophages Constitute Targets for Immunotoxic Inorganic Arsenic

Lemarié

Morzadec

Bourdonnay

et al. 2006

The Journal of Immunology

125

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Chronic exposure to inorganic arsenic, a widely distributed environmental contaminant, can lead to toxic effects, including immunosuppression. Owing to the established roles of human macrophages in immune defense, we determined, in the present study, whether inorganic arsenic can affect these major immune cells. Our results demonstrate that noncytotoxic concentrations of arsenic trioxide (As2O3), an inorganic trivalent form, markedly impair differentiated features of human blood monocyte-derived macrophages. First, treatment of macrophages with 1 μM As2O3 induced a rapid cell rounding and a subsequent loss of adhesion. These morphologic alterations were associated with a marked reorganization of actin cytoskeleton, which includes retraction of peripheral actin extensions and formation of a cortical actin ring. In addition, As2O3 reduced expression of various macrophagic surface markers, enhanced that of the monocytic marker CD14, and altered both endocytosis and phagocytosis; unexpectedly, exposure of macrophages to the metalloid also strongly potentiated expression of TNFα and IL-8 induced by LPS. Finally, like monocytes, As2O3-treated macrophages can be differentiated into dendritic-like cells. Impairment of macrophage function by As2O3 mainly resulted from activation of a RhoA/Rho-associated kinase pathway; indeed, pretreatment of macrophages with the Rho-associated kinase inhibitor Y-27632 prevented metalloid effects on cytoskeleton and phagocytosis. Moreover, As2O3 was found to increase level of the active GTP-bound form of RhoA and that of phosphorylated-Moesin, a major cytoskeleton adaptor protein involved in RhoA regulation. Taken together, our results demonstrated that human macrophages constitute sensitive targets of inorganic arsenic, which may contribute to immunotoxicity of this environmental contaminant.

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“…We hypothesized that in utero exposure to arsenic would be associated with altered epigenome-wide methylation after controlling for cell mixture. Based on experimental evidence that arsenic alters the development, activation and proliferation of T-cells, [26][27][28][29][30][31][32][33][34][35][36][37] we further hypothesized that prenatal arsenic exposure would independently influence the immune response, which would be associated with altered leukocyte subpopulations in cord blood.…”

Section: Introductionmentioning

confidence: 99%

Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood

et al. 2014

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Sodium arsenite retards proliferation of PHA-activated T cells by delaying the production and secretion of IL-2

Cited by 47 publications

References 41 publications

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway

Human Macrophages Constitute Targets for Immunotoxic Inorganic Arsenic

Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood

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