Critical function of T cell death-associated gene 8 in glucocorticoid-induced thymocyte apoptosis

Tosa, Noriko; Murakami, Masaaki; Jia, Wen; Yokoyama, Minesuke; Masunaga, Taro; Iwabuchi, Chikako; Inobe, Manabu; Iwabuchi, Kazuya; Miyazaki, Tatsuya; Onoé, Kazunori; Iwata, Makoto; Uede, Toshimitsu

doi:10.1093/intimm/dxg070

Cited by 57 publications

(51 citation statements)

References 53 publications

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“…Many of the dexamethasoneinduced genes found in this study have been previously reported in similar screens, including Tdag8, 18,19 Fkbp51, 19 Dig2 20 and Bim. 19,20 Overexpression of these genes changes susceptibility to apoptosis and also changes sensitivity to dexamethasone in a variety of systems.…”

Section: Resultssupporting

confidence: 83%

“…It is worth noting that in order to identify Tnfaip8 as crucial we used both overexpression and downregulation of expression. It is essential to do both as overexpression of Tdag8 in thymocytes suggested that it may have an essential role in thymocyte apoptosis; 18 however, thymocytes from Tdag8 À/À mice have no enhanced protection against glucocorticoidmediated cell death. 24 Materials and Methods Microarray analysis.…”

Section: Discussionmentioning

confidence: 99%

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Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes

et al. 2009

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Glucocorticoids have significant immunoregulatory actions on thymocytes and T cells and act by binding and activating cytosolic glucocorticoid receptors, which translocate to the nucleus and control gene expression through binding to specific response elements in target genes. Glucocorticoids promote cell death by activating an apoptotic program that requires transcriptional regulation. We set out to identify genes that are crucial to the process of glucocorticoid-mediated thymocyte apoptosis. Freshly isolated murine primary thymocytes were treated with dexamethasone, mRNA isolated and used to screen DNA microarrays. A set of candidate genes with upregulated expression was identified and selected members assayed in reconstituted fetal thymic organ culture (FTOC). Fetal liver-derived hematopoietic progenitor cells (HPCs) were infected with retroviruses expressing individual genes then used to repopulate depleted fetal thymic lobes. Reconstituted FTOCs expressing the gene Tnfaip8 were treated with dexamethasone and shown to be greatly sensitized to dexamethasone. Retrovirus-mediated RNA interference was applied to knock down Tnfaip8 expression in HPCs and these were used to reconstitute FTOCs. We observed that downregulating the expression of Tnfaip8 alone was sufficient to effectively protect thymocytes against glucocorticoid-induced apoptosis. We propose that Tnfaip8 is crucial in regulating glucocorticoid-mediated apoptosis of thymocytes.

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Section: Resultssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes

et al. 2009

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“…However, its transfection significantly induced the caspase 3 activity in these cells in both the presence and the absence of psychosine (Fig. 8F), which is in agreement with previous studies (42)(43)(44). Altogether, these sets of experiments clearly demonstrate that psychosine-mediated AA release and LPC generation is independent of TDAG8.…”

Section: Deda Attenuated Psychosine-mediated Oligodendrocyte Cell Deathsupporting

confidence: 91%

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Giri

Khan

Rattan

et al. 2006

Journal of Lipid Research

101

122

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Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside bgalactosidase. This study underscores the mechanism of action of psychosine in the regulation of oligodendrocyte cell death via the generation of lysophosphatidylcholine (LPC) and arachidonic acid (AA) by the activation of secretory phospholipase A2 (sPLA2). There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with psychosine also showed the generation of LPC and the release of AA in a dose-and time-dependent manner, indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic phospholipase A2 and sPLA2 and psychosine-mediated induction of sPLA2 enzymatic activity in media supernatant suggest that psychosine-induced release of AA and generation of LPC is mainly contributed by sPLA2. An inhibitor of sPLA2, 7,7-dimethyl eicosadienoic acid, completely attenuated the psychosine-mediated accumulation of LPC levels, release of AA, and generation of reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and caspase 3 activity assays. This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease.-Giri, S

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“…In the case of thymocyte apoptosis, it has been previously shown that gene activation is essential to this process (6). However, the genes required for initiating the cell death program are only beginning to be uncovered (7)(8)(9)(10)(11).…”

Section: G Lucocorticoids (Gcs)mentioning

confidence: 99%

Glucocorticoids Engage Different Signal Transduction Pathways to Induce Apoptosis in Thymocytes and Mature T Cells

Wang

Müller

McPherson

et al. 2006

The Journal of Immunology

100

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Glucocorticoids (GC) induce apoptosis in a variety of cells, but their exact mode of action is controversial. Although initiation relies on the GC receptor (GR) and de novo gene expression, the effector phase differs among cell types. Proteasomal degradation as well as caspase-3, - 8, and -9 activity are essential for GC-induced apoptosis in murine thymocytes, but the same enzymes are dispensable in splenic T cells. Live imaging by confocal microscopy revealed that lysosomal cathepsin B, an unrecognized component of this pathway to date, becomes rapidly activated in thymocytes after GC exposure. This is followed by leakage of cathepsin B into the cytosol, nuclear condensation, and processing of caspase-8 and -3. According to our model, activation of caspase-3 by caspase-9 in thymocytes occurs both directly as well as indirectly via a lysosomal amplification loop. Interestingly, acute T lymphoblastic leukemia cells depend on caspase activity to undergo GC-induced cell death similar to thymocytes. Collectively, the apoptotic program induced by GCs comprises cell type-specific as well as common features.

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Critical function of T cell death-associated gene 8 in glucocorticoid-induced thymocyte apoptosis

Cited by 57 publications

References 53 publications

Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes

Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Glucocorticoids Engage Different Signal Transduction Pathways to Induce Apoptosis in Thymocytes and Mature T Cells

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