Tumor Necrosis Factor-Like Weak Inducer of Apoptosis-Induced Neurodegeneration

Potrovita, Ioana; Zhang, Wen; Burkly, Linda C.; Hahm, Kyungmin; Lincecum, John; Wang, Monica Z.; Maurer, Martin H.; Rossner, Moritz J.; Schneider, Armin; Schwaninger, Markus

doi:10.1523/jneurosci.1089-04.2004

Cited by 122 publications

(147 citation statements)

References 49 publications

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“…TWEAK contributes actively to regulation of BBB permeability and leukocyte recruitment into the brain in inflammatory conditions, and blockade of TWEAK can interfere with inflammatory recruitment into the CNS, 55 and neuronal loss. 24 Specifically, there is direct evidence that TWEAK increases the permeability of the neurovascular unit through MMP-9 expression. 20 Moreover, endothelial cells secrete CCL2, MCP-1, and IL-8, as well as up-regulate ICAM-1 and E-selectin, in response to TWEAK treatment in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…By coupling Fn14 to TRAIL, one is providing an agent that sustains the integrity of the BBB (via TWEAK blockade) and thereby mitigates TRAIL's access to the CNS. Moreover, because TWEAK has been reported to trigger neuronal cell death, 24 Fn14-TRAIL would be expected to protect neurons by blocking this TWEAK activity as well.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, TWEAK has pro-angiogenic activity, 21 which is of interest given the association between angiogenesis and autoimmune pathogenesis. 22 TWEAK increases EAE severity and associated neurodegeneration, 14,23,24 and circulating TWEAK levels are significantly increased in patients with MS and other chronic inflammatory diseases. 6 The induction of inhibitory anti-TWEAK or Fn14 antibody (Ab) in vivo, via vaccination with the extracellular domains of either TWEAK or Fn14, ameliorates EAE manifestations in rat and mouse models.…”

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confidence: 99%

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Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Razmara

Hilliard

Ziarani

et al. 2009

The American Journal of Pathology

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Hallmarks of the pathogenesis of autoimmune encephalomyelitis include perivascular infiltration of inflammatory cells into the central nervous system, multifocal demyelination in the brain and spinal cord, and focal neuronal degeneration. Optimal treatment of this complex disease will ultimately call for agents that target the spectrum of underlying pathogenic processes. In the present study, Fn14-TRAIL is introduced as a unique immunotherapeutic fusion protein that is designed to exchange and redirect intercellular signals within inflammatory cell networks, and, in so doing, to impact multiple pathogenic events and yield a net anti-inflammatory effect. In this soluble protein product, a Fn14 receptor component (capable of blocking the pro-inflammatory TWEAK ligand) is fused to a TRAIL ligand (capable of inhibiting activated, pathogenic T cells). Sustained Fn14-TRAIL expression was obtained in vivo using a transposon-based eukaryotic expression vector. Fn14-TRAIL expression effectively prevented chronic, nonremitting, paralytic disease in myelin oligodendrocyte glycoprotein-challenged C57BL/6 mice. Disease suppression in this model was reflected by decreases in the clinical score, disease incidence, nervous tissue inflammation, and Th1, Th2, and Th17 cytokine responses. Significantly, the therapeutic efficacy of Fn14-TRAIL could not be recapitulated simply by administering its component parts (Fn14 and TRAIL) as soluble agents, either alone or in combination. Its functional pleiotropism was manifest in its additional ability to attenuate the enhanced permeability of the blood-brain barrier that typically accompanies autoimmune encephalomyelitis. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Razmara

Hilliard

Ziarani

et al. 2009

The American Journal of Pathology

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“…After 10 d in vitro, cortical neurons were transfected using Lipo- (Potrovita et al, 2004). To normalize the transfection efficiency, 0.02 g per well Renilla luciferase (phRLTK) control plasmid (Promega, Mannheim, Germany) was used.…”

Section: Methodsmentioning

confidence: 99%

Bim and Noxa Are Candidates to Mediate the Deleterious Effect of the NF-κB Subunit RelA in Cerebral Ischemia

Inta¹,

Paxian²,

et al. 2006

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“…An emerging role of TWEAK is in the growth suppression of various cell types, including erythroblasts, 18 kidney mesangial cells, 26 neuronal cells, 27 NK cells 2 and monocytes. 28 TWEAK can act in concert with other TNFSF members TRAIL and CD95L, to mediate erythropoietic suppression by IFNg.…”

Section: The Involvement Of Tweak and Fn14 In Cell Deathmentioning

confidence: 99%

TWEAK shall inherit the earth

Vince

Silke

2006

Cell Death Differ

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Sometimes size really does not matter: recent papers on the tumour necrosis factor (TNF)-like ligand, TWEAK (tumour necrosis factor-like weak inducer of apoptosis), and its diminutive 129 amino-acid receptor, FN14 (fibroblast growth factor (FGF) -inducible 14 kDa protein), describe an impressive and potent range of biological effects. The TNF superfamily (TNSF) receptor FN14 has a small cytoplasmic domain, and the limited similarity of its extracellular domain to the cysteine-rich domains of the TNFSF receptors was only appreciated retrospectively when it was discovered that it bound TWEAK. 1 Recent work has demonstrated that TWEAK knockout animals have an activated immune system that is skewed by elevated numbers of natural killer (NK) cells and responds lethally to bacterial endotoxins, but also shows a powerful ability to prevent tumour growth. 2 Other topical papers show that TWEAK and FN14 work to promote liver regeneration following injury and prevent the differentiation of a diverse range of cell types. The role of TWEAK and FN14 in cancer has yet to be conclusively established, but several groups have observed high expression of FN14 in cancerous tissues, and demonstrated that it can promote cellular functions important for tumorigenesis, including cytokine production, cellular proliferation, survival, migration and angiogenesis. 3 TWEAK is a type II transmembrane protein (extracellular C-terminus) that can undergo proteolysis to produce an active soluble homotrimer, 4,5 whereas FN14 is a type Ia transmembrane protein. 6 In some respects the potent effects of the ligand TWEAK are reminiscent to those of TNFa: both factors appear to play roles in inflammation, and both have the capacity to induce cell death, although usually in conjunction with another stimulus. Responses to TNFSF ligands can be complex because several ligands often bind to the same receptor and vice versa. For example, both the human ligands TNFa and LTa bind the receptors TNFR1 and TNFR2, whereas LTa also binds HVEM. In fact, more than half of the TNSF ligands bind to at least two receptors. 7 One of the amazing things about the TWEAK/FN14 system is that it is a simple, single ligand, single receptor system 7 in which the intracellular signalling domain of FN14 is only 28 amino acids. It remains possible that another TWEAK receptor exists 8 which might help to explain the diverse range of effects that TWEAK produces, but this is yet to be conclusively established.

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Tumor Necrosis Factor-Like Weak Inducer of Apoptosis-Induced Neurodegeneration

Cited by 122 publications

References 49 publications

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Bim and Noxa Are Candidates to Mediate the Deleterious Effect of the NF-κB Subunit RelA in Cerebral Ischemia

TWEAK shall inherit the earth

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