CD40 Induces Apoptosis in Carcinoma Cells through Activation of Cytotoxic Ligands of the Tumor Necrosis Factor Superfamily

ABSTRACT CD40, a tumor necrosis factor (TNF) receptor (TNFR) family member, conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death. The ability of CD40 to mediate apoptosis in carcinoma cells is intriguing given the fact that the CD40 cytoplasmic C terminus lacks a death domain homology with the cytotoxic members of the TNFR superfamily, such as Fas, TNFR1, and TNF-related apoptosis-inducing ligand (TRAIL) receptors. In this study, we have probed the mechanism by which CD40 transduces death signals. Using a trimeric recombinant soluble CD40 ligand to activate CD40, we have found that this phenomenon critically depends on the membrane proximal domain (amino acids 216 to 239) but not the TNFR-associated factor-interacting PXQXT motif in the CD40 cytoplasmic tail. CD40-mediated cytotoxicity is blocked by caspase inhibitors, such as zVAD-fmk and crmA, and involves activation of caspase 8 and caspase 3. Interestingly, CD40 ligation was found to induce functional Fas ligand, TRAIL (Apo-2L) and TNF in apoptosis-susceptible carcinoma cells and to up-regulate expression of Fas. These findings identify a novel proapoptotic mechanism which is induced by CD40 in carcinoma cells and depends on the endogenous production of cytotoxic cytokines and autocrine or paracrine induction of cell death.

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Uterine epithelial expression of the tumor necrosis factor superfamily: a strategy for immune privilege during pregnancy in a true epitheliochorial placentation species

Biology of Reproduction ◽

10.1093/biolre/ioz233 ◽

2020 ◽

Vol 102 (4) ◽

pp. 828-842 ◽

Cited By ~ 1

Author(s):

Inkyu Yoo ◽

Yoon Chul Kye ◽

Jisoo Han ◽

Minjeong Kim ◽

Soohyung Lee ◽

...

Keyword(s):

Cell Death ◽

Tumor Necrosis Factor ◽

Epithelial Cells ◽

Tumor Necrosis ◽

Fas Ligand ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Immune Privilege ◽

Tumor Necrosis Factor Superfamily ◽

Necrosis Factor

Abstract The maternal immune system tolerates semi-allogeneic placental tissues during pregnancy. Fas ligand (FASLG) and tumor necrosis factor superfamily 10 (TNFSF10) are known to be components of maternal immune tolerance in humans and mice. However, the role of FASLG and TNFSF10 in the tolerance process has not been studied in pigs, which form a true epitheliochorial type placenta. Thus, the present study examined the expression and function of FASLG and TNFSF10 and their receptors at the maternal-conceptus interface in pigs. The endometrium and conceptus tissues expressed FASLG and TNFSF10 and their receptor mRNAs during pregnancy in a stage-specific manner. During pregnancy, FASLG and TNFSF10 proteins were localized predominantly to endometrial luminal epithelial cells with strong signals on Day 30 to term and on Day 15, respectively, and receptors for TNFSF10 were localized to some stromal cells. Interferon-γ (IFNG) increased the expression of TNFSF10 and FAS in endometrial tissues. Co-culture of porcine endometrial epithelial cells over-expressing TNFSF10 with peripheral blood mononuclear cells yielded increased apoptotic cell death of lymphocytes and myeloid cells. In addition, many apoptotic T cells were found in the endometrium on Day 15 of pregnancy. The present study demonstrated that FASLG and TNFSF10 were expressed at the maternal-conceptus interface and conceptus-derived IFNG increased endometrial epithelial TNFSF10, which, in turn, induced apoptotic cell death of immune cells. These results suggest that endometrial epithelial FASLG and TNFSF10 may be critical for the formation of micro-environmental immune privilege at the maternal-conceptus interface for the establishment and maintenance of pregnancy in pigs.

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The role of apoptosis-inducing receptors of the tumor necrosis factor family in thyroid cancer

Journal of Endocrinology ◽

10.1677/joe.0.1780205 ◽

2003 ◽

Vol 178 (2) ◽

pp. 205-216 ◽

Cited By ~ 27

Author(s):

CS Mitsiades ◽

V Poulaki ◽

N Mitsiades

Keyword(s):

Thyroid Cancer ◽

Tumor Necrosis Factor ◽

Thyroid Carcinoma ◽

Tumor Necrosis ◽

Fas Ligand ◽

Carcinoma Cells ◽

The Other ◽

Tnf Alpha ◽

Other Hand ◽

Necrosis Factor

The tumor necrosis factor (TNF) family comprises several ligands, such as the prototype TNF-alpha, the Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), which trigger apoptosis in susceptible cells by activating respective cell-surface receptors. The study of these cell death pathways has attracted significant attention in several fields, including that of thyroid cancer, because they participate in immune system function, as an arm of cell-mediated cytotoxicity, and because recombinant ligands are available for pharmacological use. TNF-alpha is a pluripotent cytokine that induces both pro-apoptotic and anti-apoptotic effects on thyroid carcinoma cells. FasL triggers apoptosis in other tumor types, but thyroid carcinoma cells are resistant to this effect. On the other hand, TRAIL potently and selectively kills thyroid carcinoma cells. Consequently, TRAIL is the only member of the family with significant anticancer activity and an acceptable toxicity profile to be used as a novel therapy for thyroid cancer. The caspase inhibitor FLIP plays a significant role in negatively regulating receptor-induced apoptosis. Thelper 1-type cytokines, such as interferon-gamma, TNF-alpha and interleukin-1beta increase the sensitivity of both normal and neoplastic thyrocytes to FasL and TRAIL. On the other hand, IGF-I and other growth/survival factors produced in the local tumor microenvironment activate the phosphatidylinositol 3-kinase/Akt kinase pathway and exert an anti-apoptotic effect by upregulating several apoptosis inhibitors, including FLIP. Pharmacological modulation of apoptosis induced by FasL and TRAIL/Apo2L holds promise of therapeutic applications in human malignancies.

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The C-terminal Tails of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) and Fas Receptors Have Opposing Functions in Fas-associated Death Domain (FADD) Recruitment and Can Regulate Agonist-specific Mechanisms of Receptor Activation

Journal of Biological Chemistry ◽

10.1074/jbc.m409578200 ◽

2004 ◽

Vol 279 (50) ◽

pp. 52479-52486 ◽

Cited By ~ 44

Author(s):

Lance R. Thomas ◽

Ronald L. Johnson ◽

John C. Reed ◽

Andrew Thorburn

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Molecular Mechanisms ◽

Death Receptor ◽

Receptor Activation ◽

Death Domain ◽

Absolute Requirement ◽

Trail Receptors ◽

Domain Interactions ◽

Necrosis Factor

Members of the tumor necrosis factor (TNF) superfamily of receptors such as Fas/CD95 and the TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5 induce apoptosis by recruiting adaptor molecules and caspases. The central adaptor molecule for these receptors is a death domain-containing protein, FADD, which binds to the activated receptor via death domain-death domain interactions. Here, we show that in addition to the death domain, the C-terminal tails of DR4 and DR5 positively regulate FADD binding, caspase activation and apoptosis. In contrast, the corresponding region in the Fas receptor has the opposite effect and inhibits binding to the receptor death domain. Replacement of wild-type or mutant DR5 molecules into DR5-deficient BJAB cells indicates that some agonistic antibodies display an absolute requirement for the C-terminal tail for FADD binding and signaling while other antibodies can function in the absence of this mechanism. These data demonstrate that regions outside the death domains of DR4 and DR5 have opposite effects to that of Fas in regulating FADD recruitment and show that different death receptor agonists can use distinct molecular mechanisms to activate signaling from the same receptor.

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Reactive Nitrogen Species-Induced Cell Death Requires Fas-Dependent Activation of c-Jun N-Terminal Kinase

Molecular and Cellular Biology ◽

10.1128/mcb.24.15.6763-6772.2004 ◽

2004 ◽

Vol 24 (15) ◽

pp. 6763-6772 ◽

Cited By ~ 45

Author(s):

Punya Shrivastava ◽

Cristen Pantano ◽

Richard Watkin ◽

Brian McElhinney ◽

Amy Guala ◽

...

Keyword(s):

Cell Death ◽

Tumor Necrosis Factor ◽

Reactive Nitrogen Species ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Reactive Nitrogen ◽

Death Domain ◽

Nitrogen Species ◽

Jnk Activation ◽

Necrosis Factor

ABSTRACT Nitrogen dioxide is a highly toxic reactive nitrogen species (RNS) recently discovered as an inflammatory oxidant with great potential to damage tissues. We demonstrate here that cell death by RNS was caused by c-Jun N-terminal kinase (JNK). Activation of JNK by RNS was density dependent and caused mitochondrial depolarization and nuclear condensation. JNK activation by RNS was abolished in cells lacking functional Fas or following expression of a truncated version of Fas lacking the intracellular death domain. In contrast, RNS induced JNK potently in cells expressing a truncated version of tumor necrosis factor receptor 1 or cells lacking tumor necrosis factor receptor 1 (TNF-R1), illustrating a dependence of Fas but not TNF-R1 in RNS-induced signaling to JNK. Furthermore, Fas was oxidized, redistributed, and colocalized with Fas-associated death domain (FADD) in RNS-exposed cells, illustrating that RNS directly targeted Fas. JNK activation and cell death by RNS occurred in a Fas ligand- and caspase-independent manner. While the activation of JNK by RNS or FasL required FADD, the cysteine-rich domain 1 containing preligand assembly domain required for FasL signaling was not involved in JNK activation by RNS. These findings illustrate that RNS cause cell death in a Fas- and JNK-dependent manner and that this occurs through a pathway distinct from FasL. Thus, avenues aimed at preventing the interaction of RNS with Fas may attenuate tissue damage characteristic of chronic inflammatory diseases that are accompanied by high levels of RNS.

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Fas-associated Death Domain Protein (FADD) and Caspase-8 Mediate Up-regulation of c-Fos by Fas Ligand and Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) via a FLICE Inhibitory Protein (FLIP)-regulated Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m100444200 ◽

2001 ◽

Vol 276 (35) ◽

pp. 32585-32590 ◽

Cited By ~ 48

Author(s):

Daniela Siegmund ◽

Davide Mauri ◽

Nathalie Peters ◽

Peter Juo ◽

Margot Thome ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Fas Ligand ◽

Caspase 8 ◽

Death Domain ◽

Inhibitory Protein ◽

Domain Protein ◽

Necrosis Factor

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The Death Domain Kinase RIP Protects Thymocytes from Tumor Necrosis Factor Receptor Type 2–induced Cell Death

Journal of Experimental Medicine ◽

10.1084/jem.20011470 ◽

2002 ◽

Vol 196 (1) ◽

pp. 15-26 ◽

Cited By ~ 45

Author(s):

Nicole Cusson ◽

Sarah Oikemus ◽

Elizabeth D. Kilpatrick ◽

Leslie Cunningham ◽

Michelle Kelliher

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Receptor Activation ◽

Death Domain ◽

Necrosis Factor

Fas and the tumor necrosis factor receptor (TNFR)1 regulate the programmed cell death of lymphocytes. The death domain kinase, receptor interacting protein (rip), is recruited to the TNFR1 upon receptor activation. In vitro, rip−/− fibroblasts are sensitive to TNF-induced cell death due to an impaired nuclear factor κB response. Because rip−/− mice die at birth, we were unable to examine the effects of a targeted rip mutation on lymphocyte survival. To address the contribution of RIP to immune homeostasis, we examined lethally irradiated mice reconstituted with rip−/− hematopoietic precursors. We observed a decrease in rip−/− thymocytes and T cells in both wild-type C57BL/6 and recombination activating gene 1−/− irradiated hosts. In contrast, the B cell and myeloid lineages are unaffected by the absence of rip. Thus, the death domain kinase rip is required for T cell development. Unlike Fas-associated death domain, rip does not regulate T cell proliferation, as rip−/− T cells respond to polyclonal activators. However, rip-deficient mice contain few viable CD4+ and CD8+ thymocytes, and rip−/− thymocytes are sensitive to TNF-induced cell death. Surprisingly, the rip-associated thymocyte apoptosis was not rescued by the absence of TNFR1, but appears to be rescued by an absence of TNFR2. Taken together, this study implicates RIP and TNFR2 in thymocyte survival.

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Competitive Control of Independent Programs of Tumor Necrosis Factor Receptor-Induced Cell Death by TRADD and RIP1

Molecular and Cellular Biology ◽

10.1128/mcb.26.9.3505-3513.2006 ◽

2006 ◽

Vol 26 (9) ◽

pp. 3505-3513 ◽

Cited By ~ 93

Author(s):

Lixin Zheng ◽

Nicolas Bidere ◽

David Staudt ◽

Alan Cubre ◽

Jan Orenstein ◽

...

Keyword(s):

Cell Death ◽

Tumor Necrosis Factor ◽

Cell Fate ◽

Tumor Necrosis ◽

Immune Cell ◽

Inflammatory Responses ◽

Tumor Necrosis Factor Receptor ◽

Cell Types ◽

Death Domain ◽

Necrosis Factor

ABSTRACT Stimulation of tumor necrosis factor receptor 1 (TNFR1) can initiate several cellular responses, including apoptosis, which relies on caspases, necrotic cell death, which depends on receptor-interacting protein kinase 1 (RIP1), and NF-κB activation, which induces survival and inflammatory responses. The TNFR-associated death domain (TRADD) protein has been suggested to be a crucial signal adaptor that mediates all intracellular responses from TNFR1. However, cells with a genetic deficiency of TRADD are unavailable, precluding analysis with mature immune cell types. We circumvented this problem by silencing TRADD expression with small interfering RNA. We found that TRADD is required for TNFR1 to induce NF-κB activation and caspase-8-dependent apoptosis but is dispensable for TNFR1-initiated, RIP1-dependent necrosis. Our data also show that TRADD and RIP1 compete for recruitment to the TNFR1 signaling complex and the distinct programs of cell death. Thus, TNFR1-initiated intracellular signals diverge at a very proximal level by the independent association of two death domain-containing proteins, RIP1 and TRADD. These single transducers determine cell fate by triggering NF-κB activation, apoptosis, and nonapoptotic death signals through separate and competing signaling pathways.

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