Bcl-xL overexpression decreases GILZ levels and inhibits glucocorticoid-induced activation of caspase-8 and caspase-3 in mouse thymocytes

Abstract

Glucocorticoids promote thymocyte apoptosis and modulate transcription of numerous regulators of thymic apoptosis. Among these, glucocorticoid-induced leucine zipper (GILZ) is strongly upregulated in the thymus. We have previously demonstrated that GILZ decreases Bcl-xL expression, activates caspase-8 and caspase-3, and augments apoptosis in mice thymocytes. To better understand the causal links between glucocorticoids, GILZ, Bcl-xL, caspase-8, and caspase-3, we analyzed the thymocytes of Bcl-xL-overexpressing transgenic mice with or without glucocorticoid stimulation in vitro . Overexpression of Bcl-xL inhibited the glucocorticoid-induced up-regulation of GILZ in murine thymocytes as well as the glucocorticoid-dependent activation of caspase-8 and caspase-3. By contrast, no appreciable change in caspase-9 activation was observed upon Bcl-xL overexpression. Thus, these experiments highlighted a novel thymocyte apoptotic pathway in which Bcl-xL overexpression inhibited the glucocorticoid-induced activation of caspase-8 and caspase-3, but not caspase-9, as well as the accumulation of GILZ protein. These findings, together with our previous results showing that caspase-8 protects GILZ from proteasomal degradation, suggest the presence of a glucocorticoid-induced apoptosis self-amplification loop in which GILZ decreases Bcl-xL expression with a subsequent activation of caspase-8 and caspase-3; caspase-8 activation then enhances the stability and accumulation of GILZ and ensures the unimpeded and irreversible progression of apoptosis. By contrast, inappropriate increases in Bcl-xL levels could have catastrophic effects on thymic apoptosis as it would shut down caspase-8/3 activation, diminish the expression of GILZ, and impair the fine control necessary for thymic generation of a healthy immune repertoire.

Cytotoxic and anticancer activity of a novel synthesized tet-AuNPs simultaneously activates p53 and inhibits NF-kB signaling in SKBR3 cell line

“…On the other hand, death receptors activate the caspase 8, which later is activates caspase 3 [24]. Henceforth, caspase 3 activates the intrinsic pathway [24]. In our study, the fold increase in caspase 9, 8 and 3 mRNA expression were very minute in CRL-4010 normal cells, whereas that in SKBR3 cells became upregulated by more than 4 folds, emphasizing the more selective action of AuNPs on cancer cells (Fig.…”

“…Apaf1 stimulates caspase 9 which causes activation of caspase 3 that plays a crucial role in cell death [23]. On the other hand, death receptors activate the caspase 8, which later is activates caspase 3 [24]. Henceforth, caspase 3 activates the intrinsic pathway [24].…”

Induction of ligustrazine apoptosis of A549 cells through activation of death receptor pathway

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Glucocorticoid-Induced Leucine Zipper-Mediated TLR2 Downregulation Accounts for Reduced Neutrophil Activity Following Acute DEX Treatment

“…Several studies have demonstrated that GILZ exerts anti-inflammatory activity, often acting as a mediator of glucocorticoid actions but without the glucocorticoid-derived side effects [ 6 , 7 , 8 , 9 , 10 ]. While almost ubiquitously expressed, GILZ is rapidly induced by glucocorticoids primarily in immune cells of the adaptive and innate system and regulates their cellular functions (e.g., activation, differentiation, and apoptosis) [ 3 , 11 , 12 , 13 , 14 , 15 , 16 ]. Within the cells of the innate immune system, few studies have investigated the function of GILZ in neutrophils.…”