A Novel Signaling Mechanism for Soluble CD95 Ligand

Xiao, Sheng; Jodo, Satoshi; Sung, Sun-sang J.; Marshak‐Rothstein, Ann; Ju, Shyr‐Te

doi:10.1074/jbc.m206093200

Cited by 21 publications

(10 citation statements)

References 49 publications

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“… 15 Likewise, it has been found that poorly active, soluble CD95L trimers synergistically induce cell death with non-apoptotic CD95-specific antibodies and that some CD40-specific antibodies enhance soluble CD40L activity. 58 , 70 Of course, a straightforward explanation of these observations is that these TNFRSF receptor antibodies bring together individually assembled trimeric ligand–receptor complexes.…”

Section: Relevance Of Isotype and Oligomerization For Agonistic Activmentioning

confidence: 99%

Principles of antibody-mediated TNF receptor activation

2015

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From the beginning of research on receptors of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF), agonistic antibodies have been used to stimulate TNFRSF receptors in vitro and in vivo. Indeed, CD95, one of the first cloned TNFRSF receptors, was solely identified as the target of cell death-inducing antibodies. Early on, it became evident from in vitro studies that valency and Fcγ receptor (FcγR) binding of antibodies targeting TNFRSF receptors can be of crucial relevance for agonistic activity. TNFRSF receptor-specific antibodies of the IgM subclass and secondary cross-linked or aggregation prone dimeric antibodies typically display superior agonistic activity compared with dimeric antibodies. Likewise, anchoring of antibodies to cell surface-expressed FcγRs potentiate their ability to trigger TNFRSF receptor signaling. However, only recently has the relevance of oligomerization and FcγR binding for the in vivo activity of antibody-induced TNFRSF receptor activation been straightforwardly demonstrated in vivo. This review discusses the crucial role of oligomerization and/or FcγR binding for antibody-mediated TNFRSF receptor stimulation in light of current models of TNFRSF receptor activation and especially the overwhelming relevance of these issues for the rational development of therapeutic TNFRSF receptor-targeting antibodies.

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Section: Relevance Of Isotype and Oligomerization For Agonistic Activmentioning

confidence: 99%

Principles of antibody-mediated TNF receptor activation

2015

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“…In addition to the regulation of apoptosis, Fas-FasL interaction has also been shown to play a prominent role in the activation of NF-κB [68,69] and the induction of inflammatory response [70,71,72]. These distinct effects of FasL may result from the functional differences in membrane-anchored and soluble form of this molecule.…”

Section: Fas/fas Ligandmentioning

confidence: 99%

Cytotoxic Proteins and Therapeutic Targets in Severe Cutaneous Adverse Reactions

Chung

2014

Toxins

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Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are rare but life-threatening conditions induced mainly by a variety of drugs. Until now, an effective treatment for SJS/TEN still remains unavailable. Current studies have suggested that the pathobiology of drug-mediated SJS and TEN involves major histocompatibility class (MHC) I-restricted activation of cytotoxic T lymphocytes (CTLs) response. This CTLs response requires several cytotoxic signals or mediators, including granulysin, perforin/granzyme B, and Fas/Fas ligand, to trigger extensive keratinocyte death. In this article, we will discuss the cytotoxic mechanisms of severe cutaneous adverse reactions and their potential applications on therapeutics for this disease.

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“…Indeed, sFasL is capable of activating the NF-κB pathway (Supplementary Fig. 1 and 18,19). We sought to determine the physiological functions of mFasL and sFasL by generating gene-targeted mice that cannot shed FasL but do express membrane-bound FasL ( FasL Δs/Δs ) or conversely mice that lack membrane-bound FasL but are capable of producing sFasL ( FasL Δm/Δm ).…”

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confidence: 99%

“…If sFasL plays a role in inflammation, for example through NF-κB activation (Supplementary Fig. 1 and 18,19), one would expect significant differences in morbidity and mortality between FasL Δm/Δm and FasL gld/gld mice. It was therefore remarkable that FasL Δm/Δm mice became sick significantly earlier than FasL gld/gld mice (Fig.…”

mentioning

confidence: 99%

“…FasL was shown to activate NF-κB transcription factors and expression of pro-inflammatory cytokines and chemokines (Supplementary Fig. 1 5,18,19). We therefore hypothesised that FasL Δm/Δm mice may develop autoimmune disease more rapidly and at higher incidence than FasL gld/gld animals because only the former produce excess sFasL that can bind to its receptor Fas, which may then activate NF-κB and thereby drive production of pro-inflammatory cytokines (Supplementary Figs.…”

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confidence: 99%

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Membrane-bound Fas ligand only is essential for Fas-induced apoptosis

Reilly

Tai

Lee

et al. 2009

Nature

351

294

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Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family and its receptor, Fas, are critical for shutdown of chronic immune responses1-3 and prevention of autoimmunity4,5. Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice6,7 and humans8,9. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding10,11. We generated gene-targeted mice that selectively lack either secreted FasL (ΔsFasL) or membrane-bound FasL (ΔmFasL) to resolve which of these forms is required for cell killing and to explore their hypothetical non-apoptotic activities. Mice lacking sFasL (FasLΔs/Δs) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasLΔm/Δm) could not kill cells through Fas activation. FasLΔm/Δm mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasLgld/gld mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, (on a C57BL/6 background) FasLΔm/Δm mice succumbed to SLE-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and considerably later in FasLgld/gld mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.

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A Novel Signaling Mechanism for Soluble CD95 Ligand

Cited by 21 publications

References 49 publications

Principles of antibody-mediated TNF receptor activation

Principles of antibody-mediated TNF receptor activation

Cytotoxic Proteins and Therapeutic Targets in Severe Cutaneous Adverse Reactions

Membrane-bound Fas ligand only is essential for Fas-induced apoptosis

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