Organotin-Induced Caspase Activation and Apoptosis in Human Peripheral Blood Lymphocytes

Stridh, Hélène; Cotgreave, Ian A.; Müller, Malin; Orrenius, Sten; Gigliotti, Dulceaydee

doi:10.1021/tx000156c

Cited by 48 publications

(28 citation statements)

References 33 publications

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“…Recently, it was reported that eosinophils contain a small number of mitochondria-like structures, lacking functional respiration, but with a suggested role to participate in the apoptotic process [17]. Tributyltin (TBT) is a potent inducer of caspase activation and apoptosis in human leukaemia T cell lines and human peripheral T lymphocytes [18][19][20][21][22]. The caspase activation is preceded by early mitochondrial changes, including rapid loss of mitochondrial membrane potential (Dy m ) and release of cytochrome c. Preincubation with the adenine nucleotide translocator (ANT)-inhibitor, bongkrekic acid (BA), blocked TBT-induced mitochondrial changes and apoptosis in Jurkat cells, suggesting that TBT induces mitochondrial permeability transition (MPT) specifically in these cells [21].…”

Section: Discussionmentioning

confidence: 99%

Caspase activation in the absence of mitochondrial changes in granulocyte apoptosis

Nopp¹,

Lundahl²,

Stridh

2002

Clinical and Experimental Immunology

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SUMMARY Eosinophils and neutrophils are two different types of granulocytes evolved from a common haematopoetic precursor in the bone marrow. Eosinophils are mainly involved in parasitic infection and allergic inflammation while neutrophils mainly participate in the defence against bacterial infections. Prolongation of granulocyte life span by inhibition of apoptosis may lead to tissue load of cells, and this has been detected in different inflammatory reactions. The molecular mechanisms and the potential role of the mitochondria in granulocyte apoptosis are poorly understood. In the present study we have characterized further the role of the mitochondria in granulocyte-apoptosis by studying the sequence of mitochondrial permeability transition (MPT) induction, loss of mitochondrial membrane potential (Δψm) and release of cytochrome c. This was made possible by applying tributyltin (TBT), a well-characterized apoptotic stimulus and MPT-inducer. We also studied potential differences in apoptosis-susceptibility between eosinophils and neutrophils. Ten minutes of TBT-exposure resulted in a substantial caspase-3 activity in both eosinophils and neutrophils, followed by phosphatidylserine (PS)-exposure after 30–120 min. Interestingly, caspase-3 activity was not preceded by MPT-induction, loss of Δψm or by cytochrome c-release in either eosinophils or neutrophils. In conclusion, we have demonstrated an extremely rapid induction of caspase-3 activity and apoptosis in human blood granulocytes without prior mitochondrial changes, including loss of mitochondrial membrane potential and release of cytochrome c. Our results open the possibility for a mitochondrial-independent activation of caspase 3 and subsequent apoptosis in granulocytes.

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Section: Discussionmentioning

confidence: 99%

Caspase activation in the absence of mitochondrial changes in granulocyte apoptosis

Nopp¹,

Lundahl²,

Stridh

2002

Clinical and Experimental Immunology

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“…Because it has been suggested that organotin-induced deletion of peripheral lymphocytes is likely a component in the overall risk for immunotoxic responses in exposed humans [24], we attempted to reveal the mechanism of the transient reduction in peripheral lymphocytes induced by TPT and TBT. Although we could detect transient decreases of peripheral lymphocytes in blood from Dex-, TPT-and TBT-treated mice, we could not observe the characteristics of apoptosis or necrosis, such as DNA laddering or staining patterns for annexin V and PI, in the peripheral lymphocytes isolated from these mice in vivo at any time after administration.…”

Section: Discussionmentioning

confidence: 99%

“…However, various studies have shown that organotins at high doses induce apoptosis in rat thymocytes in vitro and in vivo [2,5,7,15,17,20] and suggest that exposure to TPT and TBT actually triggers apoptosis, rather than being directly cytotoxic. Moreover, Stridh et al reported that TBT can induce caspase activation and apoptosis in human peripheral lymphocytes in vitro and suggested that TBT-induced deletion of peripheral lymphocytes is likely a component in the overall risk for immunotoxic responses in exposed humans [24]. Therefore, the participation of apoptosis induced by these organotin compounds has been a major theme in toxicological evaluation of organotins, although the relative contribution of apoptosis to the reduction of peripheral lymphocytes and thymus atrophy in whole body in vivo experiments remains unclear.…”

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confidence: 99%

Reduction in Peripheral Lymphocytes and Thymus Atrophy Induced by Organotin Compounds In Vivo

et al. 2009

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ABSTRACT. To clarify the involvement of apoptosis in the immunotoxicity of organotin compounds, we examined the induction of apoptosis in the peripheral lymphocytes and thymus of mice treated with triphenyltin (TPT), tributyltin (TBT) or dexamethasone (Dex). Application of TPT or TBT and Dex resulted in a transient reduction in peripheral lymphocytes at 3 to 6 hr, and thymus atrophy was observed at 6 and 24 hr after administration. Lymphocyte subpopulation analysis showed that TPT and TBT induced a greater reduction in B cells than in T cells. The maximum levels of organotin in the blood were about 450 ng TPT/ml in the TPT-treated mice, and 170 ng TBT/ml in the TBT-treated mice. When the isolated peripheral lymphocytes were incubated with the organotins at 500 ng/ml, TPT and TBT induced necrosis in over 70% of cells, while both organotins caused lower percentages of apoptosis as well as necrosis after 3 hr at 100 ng/ml. In the thymus, although in vivo treatment of mice with Dex caused apoptosis, neither apoptotic nor necrotic thymocytes were observed in the TPT-and TBT-treated mice, indicating that the thymus atrophy might be caused by the antiproliferative effects of these organotin compounds. Thus, our results did not support the idea that apoptosis played a decisive part in the immunotoxicity of the organotin compounds in vivo.KEY WORDS: organotin compounds, peripheral lymphocytes, thymus atrophy.

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“…In addition, apoptosis, one of the mechanisms of cell death, is closely related to TNFα (30). TBT induces apoptosis in several kinds of cells (13)(14)(15)(16)(17)(18). We hypothesized that TBT induces apoptosis in macrophages, and that the mechanism of the apoptosis induced by TBT is related to TNFα or c-jun.…”

Section: Discussionmentioning

confidence: 99%

“…Low levels of TBT induced cell death of lymphocytes. TBT has induced apoptosis and caspase activation in human leukemia T cells (14,15), peripheral T lymphocytes (16) and rat thymocytes (17,18). However, little is known about the immunotoxicity of TBT compounds for macrophages.…”

Section: Introductionmentioning

confidence: 99%

Tributyltin (TBT) increases TNFα mRNA expression and induces apoptosis in the murine macrophage cell line in vitro

Nakano

Tsunoda

Konno

2004

Environ Health Prev Med

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Objective: Tributyltin (TBT) compounds have been widely used as antifouling agents for shipbottom paint. The immune system is a target of TBT intoxication. We evaluated the effects of TBT chloride in macrophages, which have critical roles in the immune system, using a murine macrophage lineage cell line, J774.1, in vitro.Methods: We examined tumor necrosis factor α (TNFα), interleukin-1β (IL-1β) and c-jun mRNA expression in J774.1 cells. The effects of TBT on the apoptosis of J774.1 cells were examined by determining the percentage of TUNEL-positive cells and caspase-3 activity.Results: The mean values of the viabilities of J774.1 cells exposed to TBT decreased dose-dependently. The relative mRNA expression of TNFα increased dose-dependently, however, that of IL-1β was not significantly different among the groups. The mean percentage of TUNEL-positive cells increased dose-dependently. Increases in the caspase-3 activities of J774.1 cells were observed in the groups exposed to higher concentrations of TBT. The mean value of relative mRNA expression of c-Jun transcription factor increased dose-dependently.Conclusions: The increases in the percentage of TUNEL-positive cells and in caspase-3 activity suggested that exposure to TBT induces apoptosis of J774.1 cells. The increases in the mRNA expression of TNFα and c-jun by TBT may be related to apoptosis in macrophages.

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Organotin-Induced Caspase Activation and Apoptosis in Human Peripheral Blood Lymphocytes

Cited by 48 publications

References 33 publications

Caspase activation in the absence of mitochondrial changes in granulocyte apoptosis

Caspase activation in the absence of mitochondrial changes in granulocyte apoptosis

Reduction in Peripheral Lymphocytes and Thymus Atrophy Induced by Organotin Compounds In Vivo

Tributyltin (TBT) increases TNFα mRNA expression and induces apoptosis in the murine macrophage cell line in vitro

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