TRAIL and immunity: more than a license to kill tumor cells

Corazza, Nadia; Brumatti, Gabriela; Schär, Christoph; Cima, Igor; Wasem, Christoph; Brunner, Thomas

doi:10.1038/sj.cdd.4401542

Cited by 13 publications

(13 citation statements)

References 36 publications

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“…However, the outcome of TRAIL exposure in untransformed cells is currently less understood and is controversial (24), and our data support the notion that liver damage is one of the potential risks of TRAIL-based antitumor therapy. Previous reports have shown that TRAIL may induce apoptosis in human hepatocytes (9), a finding that was not confirmed by others (16).…”

Section: Discussionsupporting

confidence: 75%

“…TRAIL-mediated modulation of apoptosis is, however, likely not limited to type II Fas signaling in hepatocytes, but may extend to other apoptosis signals proceeding via the mitochondria. It is interesting that TRAIL-deficient thymocytes show increased resistance to a variety of intrinsic apoptosis triggers, including UV and γ irradiation, glucocorticoids, and T cell receptor ligation (24,30). TRAIL signaling may therefore represent a general regulatory mechanism of the mitochondrial apoptosis pathway in different cell types.…”

Section: Discussionmentioning

confidence: 99%

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TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality

Corazza¹,

Jakob²,

Schaer³

et al. 2006

J. Clin. Invest.

116

134

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TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family with potent apoptosis-inducing properties in tumor cells. In particular, TRAIL strongly synergizes with conventional chemotherapeutic drugs to induce tumor cell death. Thus, TRAIL has been proposed as a promising future cancer therapy. Little, however, is known regarding what the role of TRAIL is in normal untransformed cells and whether therapeutic administration of TRAIL, alone or in combination with other apoptotic triggers, may cause tissue damage. In this study, we investigated the role of TRAIL in Fas-induced (CD95/Apo-1-induced) hepatocyte apoptosis and liver damage. While TRAIL alone failed to induce apoptosis in isolated murine hepatocytes, it strongly amplified Fas-induced cell death. Importantly, endogenous TRAIL was found to critically regulate anti-Fas antibody-induced hepatocyte apoptosis, liver damage, and associated lethality in vivo. TRAIL enhanced antiFas-induced hepatocyte apoptosis through the activation of JNK and its downstream substrate, the proapoptotic Bcl-2 homolog Bim. Consistently, TRAIL-and Bim-deficient mice and wild-type mice treated with a JNK inhibitor were protected against anti-Fas-induced liver damage. We conclude that TRAIL and Bim are important response modifiers of hepatocyte apoptosis and identify liver damage and lethality as a possible risk of TRAIL-based tumor therapy.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality

Corazza¹,

Jakob²,

Schaer³

et al. 2006

J. Clin. Invest.

116

134

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“…However, recent findings have shown that, depending on the activation or differentiation status, also primary normal cells can be susceptible to TRAIL-mediated apoptosis (Corazza et al, 2004). Moreover, TRAIL has been demonstrated to be an effector molecule of T cell-mediated killing of oligodendrocytes in experimental autoimmune encephalomyelitis (Aktas et al, 2005), vascular smooth muscle cells in the atherosclerotic plaque (Sato et al, 2006), or monocytes and neutrophils in lupus erythematosus systemic (Kaplan et al, 2002;Matsuyama et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Inhibition ofTrailGene Expression by Cyclopentenonic Prostaglandin 15-Deoxy-Δ^12,14-Prostaglandin J₂in T Lymphocytes

et al. 2007

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15-Deoxy-⌬12,14 -prostaglandin J 2 (15d-PGJ 2 ) is a cyclopentenonic prostaglandin endowed with powerful anti-inflammatory activities, as shown in animal models of inflammatory/autoimmune diseases, where pharmacological administration of this prostanoid can ameliorate inflammation and local tissue damage via activation of the nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR␥) and/or covalent modifications of cellular proteins. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily expressed in most of the cells, including those of immune system such as T lymphocytes, in which it is upregulated upon antigen-specific stimulation. This cytokine plays an important role in regulating various physiological and immunopathological processes, such as immunosurveillance of tumors and tissue destruction associated with different inflammatory and autoimmune diseases. Here, we demonstrate that 15d-PGJ 2 inhibits trail mRNA and protein expression by down-regulating the activity of its promoter in human T lymphocytes. Our data indicate that both the chemically reactive cyclopentenone moiety of 15d-PGJ 2 and the activation of PPAR␥ may be involved in this repressive mechanism. We identified nuclear factor B (NF-B) as a direct target of the prostanoid. 15d-PGJ 2 significantly decreases the expression and/or DNA binding of c-rel, RelA, and p50 transcription factors to the NF-B1 site of trail promoter. Moreover, 15d-PGJ 2 -mediated activation of the transcription factor heat shock factor-1 may contribute to inhibit trail promoter activity in transfected Jurkat T cells. These results suggest that modulation of TRAIL gene expression by 15d-PGJ 2 in T cells may provide a novel pharmacological tool to modify the onset and the progression of specific autoimmune and inflammatory disorders.

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“…Five TRAIL receptors have been identified of which two, TRAIL-receptor 1 (TRAIL-R1)/DR4 and TRAIL-R2/DR5, are capable of transducing an apoptotic signal whereas the other three receptors (TRAIL-R3/DcR1, TRAIL-R4/DcR2 and osteoprotegrin) lack death domains and thus cannot engage the apoptotic machinery [5,6]. TRAIL has been suggested as a safe and tumorselective anticancer agent with low toxicity to normal tissues [7,8], and is thought to play a role in tumor immune surveillance by NK, T cells and probably also cells of the innate immune system [9]. Combinations of TRAIL with chemotherapy could prove to be effective in inhibiting tumor growth in vivo [10], and the anti-TRAIL-R1 and anti-TRAIL-R2 agonistic antibodies are in phase I and II oncology trials [11].…”

Section: Introductionmentioning

confidence: 99%

TRAIL-induced survival and proliferation of SCLC cells is mediated by ERK and dependent on TRAIL-R2/DR5 expression in the absence of caspase-8

et al. 2008

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TRAIL and immunity: more than a license to kill tumor cells

Cited by 13 publications

References 36 publications

TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality

TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality

Inhibition ofTrailGene Expression by Cyclopentenonic Prostaglandin 15-Deoxy-Δ^12,14-Prostaglandin J₂in T Lymphocytes

TRAIL-induced survival and proliferation of SCLC cells is mediated by ERK and dependent on TRAIL-R2/DR5 expression in the absence of caspase-8

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TRAIL and immunity: more than a license to kill tumor cells

Cited by 13 publications

References 36 publications

TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality

TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality

Inhibition ofTrailGene Expression by Cyclopentenonic Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2in T Lymphocytes

TRAIL-induced survival and proliferation of SCLC cells is mediated by ERK and dependent on TRAIL-R2/DR5 expression in the absence of caspase-8

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Inhibition ofTrailGene Expression by Cyclopentenonic Prostaglandin 15-Deoxy-Δ^12,14-Prostaglandin J₂in T Lymphocytes