TWEAK is expressed by glial cells, induces astrocyte proliferation and increases EAE severity

Desplat‐Jégo, Sophie; Varriale, S.; Creidy, Rita; Terra, Rafik; Bernard, Dominique; Khrestchatisky, Michel; Izui, Shozo; Chicheportiche, Yves; Boucraut, José

doi:10.1016/s0165-5728(02)00368-5

Cited by 123 publications

(138 citation statements)

References 46 publications

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“…The limited nature of the literature bearing on these particular components when used as soluble agents makes it difficult to compare our findings. Although one group has reported that Ab blockade of TWEAK improves the clinical course of EAE and decreases CNS-specific inflammation, 23 the only study invoking Fn14 per se as a blocking agent involved a full-length Fn14, apparently encompassing the transmembrane and cytoplasmic regions of a rat Fn14 protein. 25 In the case of TRAIL, there is again only a single report in the literature dealing with human TRAIL and its use as a soluble agent (in this case, produced in bacteria) in an EAE therapeutic context.…”

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.…”

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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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%

mentioning

confidence: 99%

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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“…Fn14 was recently identified as a fully functional TWEAK receptor (27). This small membrane protein is able to mediate a variety of intracellular signals in a cellspecific fashion including apoptosis, necrosis, proliferation, and survival (17,22,31,43). Proliferative signals elicited by Fn14 are likely to be mediated by association of TNFR-associated factor proteins with the Fn14 cytoplasmic domain and subsequent stimulation of NF-B activity (29,30), whereas survival signals involve NF-B-mediated up-regulation of Bcl-XL and Bcl-W expression (44).…”

Section: Discussionmentioning

confidence: 99%

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

Felli

Pedini

Zeuner

et al. 2005

The Journal of Immunology

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IFN-γ inhibits the growth and differentiation of erythroid precursor cells and mediates hemopoietic suppression through mechanisms that are not completely understood. We found that treatment of human erythroid precursor cells with IFN-γ up-regulates the expression of multiple members of the TNF family, including TRAIL and the recently characterized protein TWEAK. TWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) were expressed by purified erythroblasts at all the stages of maturation. Exposure to recombinant TWEAK or agonist anti-Fn14 Abs was able to inhibit erythroid cell growth and differentiation through caspase activation. Because other members of the TNF family such as TRAIL and CD95 ligand (CD95L) are known to interfere with erythroblast growth and differentiation, we investigated the role of different TNF/TNFR family proteins as potential effectors of IFN-γ in the immature hemopoietic compartment. Treatment of erythroid precursor cells with agents that blocked either TRAIL, CD95L, or TWEAK activity was partially able to revert the effect of IFN-γ on erythroid proliferation and differentiation. However, the simultaneous inhibition of TRAIL, TWEAK, and CD95L resulted in a complete abrogation of IFN-γ inhibitory effects, indicating the requirement of different receptor-mediated signals in IFN-γ-mediated hemopoietic suppression. These results establish a new role for TWEAK and its receptor in normal and IFN-γ-mediated regulation of hematopoiesis and show that the effects of IFN-γ on immature erythroid cells depend on multiple interactions between TNF family members and their receptors.

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“…Pluchino et al 6 recently reported that upon exposure to proinflammatory cytokines, mouse NPCs express CD95 ligand (CD95L), TRAIL and TWEAK, becoming able to kill surrounding activated T cells. Although it is unlikely that TWEAK production could have any beneficial impact on the outcome of the autoimmune aggression, 7,8 the ability of mouse neural stem and progenitor cells to kill activated T cells through the production of TRAIL and CD95L can be exploited for the treatment of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. In this system, the same authors showed that the systemic injection of mouse adult NPCs promoted neuroprotection and myelin regeneration by inducing apoptosis of encephalitogenic T cells.…”

mentioning

confidence: 99%

Human neural progenitor cells display limited cytotoxicity and increased oligodendrogenesis during inflammation

et al. 2006

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TWEAK is expressed by glial cells, induces astrocyte proliferation and increases EAE severity

Cited by 123 publications

References 46 publications

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

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

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

Human neural progenitor cells display limited cytotoxicity and increased oligodendrogenesis during inflammation

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