Tributyltin exposure causes decreased granzyme B and perforin levels in human natural killer cells

Thomas, LeeShawn D

doi:10.1016/s0300-483x(04)00234-3

Cited by 6 publications

(7 citation statements)

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“…In contrast, it has been reported that CRE sequences are necessary and sufficient for transcriptional activation of the granzyme B promoter in immortalized T cell lines and primary T cells (60). Indeed, a decreased CREB phosphorylation was correlated with a decrease in granzyme B transcription in NK cells (61). CRE sequences are also found in the perforin promoter (62).…”

Section: Discussionmentioning

confidence: 93%

Circadian Oscillations of Clock Genes, Cytolytic Factors, and Cytokines in Rat NK Cells

Arjona

Sarkar

2005

The Journal of Immunology

188

141

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A growing body of knowledge is revealing the critical role of circadian physiology in the development of specific pathological entities such as cancer. NK cell function participates in the immune response against infection and malignancy. We have reported previously the existence of a physiological circadian rhythm of NK cell cytolytic activity in rats, suggesting the existence of circadian mechanisms subjacent to NK cell function. At the cellular level, circadian rhythms are originated by the sustained transcriptional-translational oscillation of clock genes that form the cellular clock apparatus. Our aim in this study was to investigate the presence of molecular clock mechanisms in NK cells as well as the circadian expression of critical factors involved in NK cell function. For that purpose, we measured the circadian changes in the expression of clock genes (Per1, Per2, Bmal1, Clock), Dbp (a clock-controlled output gene), CREB (involved in clock signaling), cytolytic factors (granzyme B and perforin), and cytokines (IFN-γ and TNF-α) in NK cells enriched from the rat spleen. The results obtained from this study demonstrate for the first time the existence of functional molecular clock mechanisms in NK cells. Moreover, the circadian expression of cytolytic factors and cytokines in NK cells reported in this study emphasizes the circadian nature of NK cell function.

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Section: Discussionmentioning

confidence: 93%

Circadian Oscillations of Clock Genes, Cytolytic Factors, and Cytokines in Rat NK Cells

Arjona

Sarkar

2005

The Journal of Immunology

188

141

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“…NK mediated lysis of the K562 target cells is sensitive to decreases in the levels of lytic granule proteins granzyme A, granzyme B and perforin or decreases in the level the LFA-1 adhesion protein. (Arnaout 1990; Dustin and Springer 1988;Matsumoto et al 2000b; Thomas et al 2004). Normal lysis of the K562 cell line by NK cells is dependent on the perforin-granzyme pathway and reductions in the levels of these proteins can cause a reduction in the ability of NK cells to lyse K562 targets cell (Clement et al 1990;Montel et al 1995).…”

Section: Discussionmentioning

confidence: 99%

In vitro atrazine-exposure inhibits human natural killer cell lytic granule release

Rowe

Brundage

Barnett

2007

Toxicology and Applied Pharmacology

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The herbicide atrazine is a known immunotoxicant and an inhibitor of human Natural Killer (NK) cell lytic function. The precise changes in NK cell lytic function following atrazine exposure have not been fully elucidated. The current study identifies the point at which atrazine exerts its affect on the stepwise process of human NK cell mediated lyses of the K562 target cell line. Using intracellular staining of human peripheral blood lymphocytes, it was determined that a 24 h in vitro exposure to atrazine did not decrease the level of NK cell lytic proteins granzyme A, granzyme B or perforin. Thus, it was hypothesized that atrazine exposure was inhibiting the ability of the NK cells to bind to the target cell and subsequently inhibit the release of lytic protein from the NK cell. To test this hypothesis, flow cytometry and fluorescent microscopy were employed to analyze NK cell-target cell co-cultures following atrazine exposure. These assays demonstrated no significant decrease in the level of target cell binding. However, the levels of NK intracellular lytic protein retained and the amount of lytic protein released were assessed following a 4 h incubation with K562 target cells. The relative level of intracellular lytic protein was 25-50% higher, and the amount of lytic protein released was 55-65% less in atrazine treated cells than vehicle treated cells following incubation with the target cells. These results indicate that ATR exposure inhibits the ability of NK cells to lyse target cells by blocking lytic granule release without affecting the ability of the NK cell to form stable conjugates with target cells.

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“…Mammals with TBT exposure show increased incidences of tumors (Wester et al, 1990). TBT decreases the ability of human NK cells to destroy tumor cells with accompanying decreases in cytotoxic and cell surface protein expression (Dudimah et al, 2007;Thomas et al, 2004;Whalen et al, 2002). In addition, TBT both inhibits and stimulates the secretion of tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) from human lymphocytes (depending on the exposure concentration) (Hurt et al, 2013;Lawrence et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Tributyltin alters secretion of interleukin 1 beta from human immune cells

Brown

Whalen

2014

J of Applied Toxicology

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Tributyltin (TBT) has been used as a biocide in industrial applications such as wood preservation, antifouling paint, and antifungal agents. Due to its many uses, it contaminates the environment and has been found in human blood samples. Interleukin 1 beta (IL-1β) is a pro-inflammatory cytokine that promotes cell growth, tissue repair, and immune response regulation. Produced predominately by both monocytes and macrophages, IL-1β appears to increase the invasiveness of certain tumors. This study shows that TBT modifies the secretion of IL-1β from increasingly reconstituted preparations of human immune cells. IL-1β secretion was examined after 24h, 48h, or 6 day exposures to TBT in highly enriched human NK cells, monocyte-depleted (MD) peripheral blood mononuclear cells (MD-PBMCs), PBMCs, granulocytes, and a preparation combining both PBMCs and granulocytes (PBMCs+granulocytes). TBT altered IL-1β secretion from all of the cells preparations. The 200 nM concentration of TBT normally blocked the secretion of IL-1β, while lower concentrations (usually 5-50 nM) elevated secretion of IL-1β. Examination of the signaling pathway(s) responsible for the elevated secretion of IL-1β were carried out in MD-PBMCs. Pathways examined were IL-1β processing (Caspase-1), mitogen-activated protein kinases (MAPKs), and nuclear factor kappa B (NFκB). Results indicated that MAPK pathways (p44/42 and p38) appear to be the targets of TBT that lead to increased IL-1β secretion from immune cells. These results from human immune cells show IL-1β dysregulation by TBT is occurring ex vivo. Thus, potential for in vivo effects on pro-inflammatory cytokine levels may possibly be a consequence of TBT exposures.

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Tributyltin exposure causes decreased granzyme B and perforin levels in human natural killer cells

Cited by 6 publications

References 0 publications

Circadian Oscillations of Clock Genes, Cytolytic Factors, and Cytokines in Rat NK Cells

Circadian Oscillations of Clock Genes, Cytolytic Factors, and Cytokines in Rat NK Cells

In vitro atrazine-exposure inhibits human natural killer cell lytic granule release

Tributyltin alters secretion of interleukin 1 beta from human immune cells

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