Induction of the cytokine TWEAK and its receptor Fn14 in ischemic stroke

Inta, Ioana; Frauenknecht, Katrin; Dörr, Henrike; Kohlhof, Patricia; Rabsilber, Tanja M.; Auffarth, Gerd U.; Burkly, Linda C.; Mittelbronn, Michel; Hahm, Kyungmin; Sommer, Clemens; Schwaninger, Markus

doi:10.1016/j.jns.2008.08.005

Cited by 50 publications

(43 citation statements)

References 11 publications

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“…The expression of TWEAK and Fn14 increases in the ischemic brain of stroke patients [44] and in animal models of cerebral ischemia [45]. During cerebral ischemia, TWEAK/Fn14 interaction activates the transcription factor nuclear factor-κB pathway and induces the expression of MMP-9 and proinflammatory cytokines and chemokines, recruitment of neutrophils, disruption of the blood-brain barrier and neurodegeneration [17,18,45,46,47].…”

Section: Discussionmentioning

confidence: 99%

The Tumor Necrosis Factor Superfamily Members TWEAK, TNFSF15 and Fibroblast Growth Factor-Inducible Protein 14 Are Upregulated in Proliferative Diabetic Retinopathy

El‐Asrar

Hertogh²,

Nawaz³

et al. 2015

Ophthalmic Res

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Purpose: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and tumor necrosis factor superfamily member 15 (TNFSF15), members of the TNF superfamily, play important roles in the modulation of inflammation and neovascularization. TWEAK activity is mediated via binding to fibroblast growth factor-inducible molecule 14 (Fn14). We investigated the expression of TWEAK, Fn14 and TNFSF15 and the correlation between TWEAK levels and the levels of the inflammatory biomarker soluble intercellular adhesion molecule-1 (sICAM-1) in proliferative diabetic retinopathy (PDR). In addition, we examined the expression of FN14 and TNFSF15 in retinas of diabetic rats. Methods: Vitreous samples from 34 PDR and 23 nondiabetic patients were studied by enzyme-linked immunosorbent assay and Western blot analysis. Epiretinal membranes from 14 patients with PDR were studied by immunohistochemistry. The retinas of rats were examined by Western blot analysis. Results: We identified a significant increase in the expression of TWEAK, Fn14, TNFSF15 and sICAM-1 in vitreous samples from PDR patients compared to controls. A significant positive correlation was found between levels of TWEAK and levels of sICAM-1 (r = 0.3, p = 0.02). In epiretinal membranes, TWEAK and TNFSF15 protein expression was confined to vascular endothelial cells, monocytes/macrophages and myofibroblasts. Significant positive correlations were observed between the number of blood vessels expressing CD34 and the number of blood vessels expressing TWEAK (r = 0.670; p = 0.017) and TNFSF15 (r = 0.784; p = 0.001). The expression level of TNFSF15 was upregulated in the retinas of diabetic rats, whereas Fn14 was not upregulated. Conclusions: Our findings suggest that TNFSF15 and the TWEAK/Fn14 pathway are novel mediators involved in persistent inflammation and modulation of pathological neovascularization associated with PDR.

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Section: Discussionmentioning

confidence: 99%

The Tumor Necrosis Factor Superfamily Members TWEAK, TNFSF15 and Fibroblast Growth Factor-Inducible Protein 14 Are Upregulated in Proliferative Diabetic Retinopathy

El‐Asrar

Hertogh²,

Nawaz³

et al. 2015

Ophthalmic Res

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“…Early studies using murine models of focal cerebral ischemia showed that both TWEAK and Fn14 mRNA expression in ischemic brain tissue increases within hours after an ischemic insult (36–38). Importantly, there is also an increased level of these mRNAs in human infarct tissue obtained from deceased stroke patients and TWEAK levels are elevated in the serum of stroke patients (39). Functional studies using Fn14-deficient mice have indicated that TWEAK/Fn14 signaling contributes to the cell death and edema that occurs following acute cerebral ischemia (38, 40).…”

Section: Tweak/fn14 Axis-targeted Therapeutics: Inflammatory And/or Nmentioning

confidence: 99%

TWEAK/Fn14 Axis-Targeted Therapeutics: Moving Basic Science Discoveries to the Clinic

et al. 2013

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The TNF superfamily member TWEAK (TNFSF12) is a multifunctional cytokine implicated in physiological tissue regeneration and wound repair. TWEAK is initially synthesized as a membrane-anchored protein, but furin cleavage within the stalk region can generate a secreted TWEAK isoform. Both TWEAK isoforms bind to a small cell surface receptor named Fn14 (TNFRSF12A) and this interaction stimulates various cellular responses, including proliferation and migration. Fn14, like other members of the TNF receptor superfamily, is not a ligand-activated protein kinase. Instead, TWEAK:Fn14 engagement promotes Fn14 association with members of the TNFR associated factor family of adapter proteins, which triggers activation of various signaling pathways, including the classical and alternative NF-κB pathways. Numerous studies have revealed that Fn14 gene expression is significantly elevated in injured tissues and in most solid tumor types. Also, sustained Fn14 signaling has been implicated in the pathogenesis of cerebral ischemia, chronic inflammatory diseases, and cancer. Accordingly, several groups are developing TWEAK- or Fn14-targeted agents for possible therapeutic use in patients. These agents include monoclonal antibodies, fusion proteins, and immunotoxins. In this article, we provide an overview of some of the TWEAK/Fn14 axis-targeted agents currently in pre-clinical animal studies or in human clinical trials and discuss two other potential approaches to target this intriguing signaling node.

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“…Based upon in vitro and in vivo animal studies, TWEAK has been reported to participate in multiple biological functions in the CNS, such as glial cell proliferation, demyelination, proinflammatory functions differentiation of adult neural progenitor cells, permeability of the blood-brain barrier and, apoptosis, under specific experimental conditions [43]–[51]. Moreover, TWEAK/Fn14 expression is enhanced in MS [44], [52]–[54] and stroke [55].…”

Section: Introductionmentioning

confidence: 99%

BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 Proteins Are Related to Human Glioma Tumor Grade: Immunohistochemistry and Public Microarray Data Meta-Analysis

et al. 2013

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Gliomas are common and lethal tumors of the central nervous system (CNS). Genetic alterations, inflammatory and angiogenic processes have been identified throughout tumor progression; however, treatment still remains palliative for most cases. Biological research on parameters influencing cell survival, invasion and tumor heterogeneity identified several cytokines interfering in CNS inflammation, oxidative stress and malignant transformation, including TNF-superfamily (TNFSF) members. In this report we performed a meta-analysis of public gene-array data on the expression of a group of TNFSF ligands (BAFF, APRIL, TWEAK) and their receptors (BAFF-R, TACI, BCMA, Fn14) in gliomas. In addition, we investigated by immunohistochemistry (IHC) the tumor cells' expression of these ligands and receptors in a series of 56 gliomas of different grade. We show that in IHC, BAFF and APRIL as well as their cognate receptors (BCMA, TACI) and Fn14 expression correlate with tumor grade. This result was not evidenced in micro-arrays meta-analysis. Finally, we detected for the first time Fn14, BAFF, BCMA and TACI in glioma-related vascular endothelium. Our data, combined with our previous report in glioma cell lines, suggest a role for these receptors and ligands in glioma biology and advance these molecules as potential markers for the classification of these tumors to the proliferative, angiogenic or stem-like molecular subtype.

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Induction of the cytokine TWEAK and its receptor Fn14 in ischemic stroke

Cited by 50 publications

References 11 publications

The Tumor Necrosis Factor Superfamily Members TWEAK, TNFSF15 and Fibroblast Growth Factor-Inducible Protein 14 Are Upregulated in Proliferative Diabetic Retinopathy

The Tumor Necrosis Factor Superfamily Members TWEAK, TNFSF15 and Fibroblast Growth Factor-Inducible Protein 14 Are Upregulated in Proliferative Diabetic Retinopathy

TWEAK/Fn14 Axis-Targeted Therapeutics: Moving Basic Science Discoveries to the Clinic

BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 Proteins Are Related to Human Glioma Tumor Grade: Immunohistochemistry and Public Microarray Data Meta-Analysis

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