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

Wang, Dapeng; Müller, Nora; McPherson, Kirsty; Reichardt, Holger M.

doi:10.4049/jimmunol.176.3.1695

Cited by 100 publications

(81 citation statements)

References 47 publications

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“…Importantly, histone H1.2 release and cytotoxicity after dexamethasone treatment were similar in both p53 deleted and non-deleted cases. It is well known that dexamethasone induces apoptosis independently of p53, [25][26][27][28] although the ultimate apoptotic mechanism of this drug is not completely known. Our results emphasize that histone H1.2 could be an essential apoptotic signal induced by agents that act independently of p53.…”

Section: Discussionmentioning

confidence: 99%

Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment

Giné¹,

Crespo²,

Muntañola³

et al. 2008

Haematologica

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Section: Discussionmentioning

confidence: 99%

Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment

Giné¹,

Crespo²,

Muntañola³

et al. 2008

Haematologica

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“…It is possible that the presence of naturally occurring cathepsin inhibitors, such as serpins and cystatins, attenuate the cytosolic activity of cathepsins and hence LMP-driven apoptosis [78,83,92] (Fig. 1C).…”

Section: Lysosomal-mediated Apoptosismentioning

confidence: 99%

“…Cathepsin B [78] and cathepsin D [79,80] have both been shown to target cytosolic substrates following LMP in immune cells. In T cells, for example, caspase-dependent apoptosis often follows TCR stimulation by a mechanism that depends on the TNF family of death receptors (activation-induced cell death) or occurs by mechanisms independent of death inducing ligands (activated T-cell autonomous death) [81].…”

Section: Lysosomal-mediated Apoptosismentioning

confidence: 99%

“…Caspases and even cathepsins themselves may be involved in amplifying the LMP pathway of apoptosis. For example, caspase 9 (activated downstream of caspase 8) contributed to TNF-induced cell death in MEF by inducing LMP [91].It is possible that the presence of naturally occurring cathepsin inhibitors, such as serpins and cystatins, attenuate the cytosolic activity of cathepsins and hence LMP-driven apoptosis [78,83,92] (Fig. 1C).…”

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Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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The innate and adaptive immune system utilise endocytic protease activity to promote functional immune responses. Cysteine and aspartic proteases (cathepsins) constitute a subset of endocytic proteases, the immune function of which has been described extensively. Although historically these studies have focused on their role in processes such as antigen presentation and zymogen processing within the endocytic compartment, recent discoveries have demonstrated a critical role for these proteases in other intracellular compartments, and within the extracellular milieu. It has also become clear that their pattern of expression and substrate specificities are more diverse than was first envisaged. Here, we discuss recent advances addressing the role of lysosomal proteases in various aspects of the immune response. We pay attention to reports demonstrating cathepsin activity outside of its canonical endosome/lysosome microenvironment.Key words: Cathepsins . Endosomes . Immune regulation . Lysosomes IntroductionThe endosome/lysosome compartments, together with the cytosolic proteasomes, are the two major protein degradation systems in cells. Both have emerged as having many important regulatory functions in addition to their role in protein breakdown for amino acid recycling. For example, limited proteolysis within the endocytic pathway can induce activating conformational changes [1,2], release functional proteins from chaperones [3], and cleave soluble bioactive molecules from membrane-anchored precursors [4]. The concept of ''regulation through limited destruction'' is evident in many processes in innate and adaptive immunity. Endosome/lysosome-located proteases play key roles in antigen processing and presentation, cytokine regulation, NKT cell development, activation of serine protease zymogens in regulated secretory granules, integrin activation, induction of apoptosis and TLR signalling. Given that these processes may also be associated with undesirable immune responses and inflammation, the proteases involved may be considered as attractive drug targets. EnzymesEndosomes and lysosomes harbour mainly cysteine and aspartic acid proteases so-named because their active site utilises either a cysteine thiol or an aspartic acid as a key part of the catalytic site. Some endosome/lysosome located serine proteases such as cathepsin G, granzymes and thymus specific serine protease (TSSP) have important roles in the immune system; however, we focus primarily here on the cysteine and aspartic proteases. Most of the lysosomal cysteine proteases are related to papain and belong to the so-called C1 family. These include cathepsins L, S, C, F, H, B, X, K, V and W. Cathepsins D and E are also found in lysosomes but are aspartic acid proteases related to pepsin. An additional cysteine protease is found in lysosomes, which is more closely related to the caspases. This is asparaginyl endopeptidase (AEP) or legumain, a member of the C13 family. Some of these enzymes are endopeptidases (cathepsins S, L, K, F, V, D, E and AEP), where...

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“…Collectively, the apoptotic program induced by GCs is comprised of cell type-specific and shared features. 83 The biological significance of GC-induced thymocyte apoptosis remains unclear. It is reasonable to think that GCs can participate in death by neglect and age-and stressrelated thymic involution.…”

Section: Role Of Caspase-8 In Gc-induced Apoptosis In Thymocytesmentioning

confidence: 99%

Role of caspase-8 in thymus function

et al. 2013

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The thymus is the primary organ responsible for de novo generation of immunocompetent T cells that have a diverse repertoire of antigen recognition. During the developmental process, 98% of thymocytes die by apoptosis. Thus apoptosis is a dominant process in the thymus and occurs through either death by neglect or negative selection or through induction by stress/aging. Caspase activation is an essential part of the general apoptosis mechanism, and data suggest that caspases may have a role in negative selection; however, it seems more probable that caspase-8 activation is involved in death by neglect, particularly in glucocorticoid-induced thymocyte apoptosis. Caspase-8 is active in double-positive (DP) thymocytes in vivo and can be activated in vitro in DP thymocytes by T-cell receptor (TCR) crosslinking to induce apoptosis. Caspase-8 is a proapoptotic member of the caspase family and is considered an initiator caspase, which is activated upon stimulation of a death receptor (e.g., Fas), recruitment of the adaptor molecule FADD, and recruitment and subsequent processing of procaspase-8. The main role of caspase-8 seems to be pro-apoptotic and, in this review, we will discuss about the involvement of caspase-8 in (1) TCR-triggered thymic apoptosis; (2) death receptor-mediated thymic apoptosis; and (3) glucocorticoid-induced thymic apoptosis. Regarding TCR triggering, caspase-8 is active in medullary, semi-mature heat-stable antigen hi (HAS hi SP) thymocytes as a consequence of strong TCR stimulation. The death receptors Fas, FADD, and FLIP are involved upstream of caspase-8 activation in apoptosis; whereas, Bid and HDAC7 are involved downstream of caspase-8. Finally, caspase-8 is involved in glucocortocoid-induced thymocyte apoptosis through an activation loop with the protein GILZ. GILZ activates caspase-8, promoting GILZ sumoylation and its protection from proteasomal degradation.

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

Cited by 100 publications

References 47 publications

Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment

Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment

Diverse regulatory roles for lysosomal proteases in the immune response

Role of caspase-8 in thymus function

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