TWEAK/Fn14 Pathway: A Nonredundant Role in Intestinal Damage in Mice Through a TWEAK/Intestinal Epithelial Cell Axis

Dohi, Taeko; Borodovsky, Anna; Wu, Ping; Shearstone, Jeffrey R.; Kawashima, Rei; Runkel, Laura; Rajman, Luis A.; Dong, Xingwen; Scott, Martin; Michaelson, Jennifer S.; Jakubowski, Aniela; Burkly, Linda C.

doi:10.1053/j.gastro.2008.11.017

Cited by 65 publications

(82 citation statements)

References 40 publications

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“…Nevertheless, it appears that the TWEAK-Fn14 system is active in processes related to growth and remodeling of tissue and organs during development and tissue repair. In accordance with this, animal studies implicated the TWEAK-Fn14 system in liver progenitor cell proliferation (6,7), regulation of muscle development and muscle regeneration (8)(9)(10)(11), tumor-associated angiogenesis (12), and in various inflammationrelated pathologies including graft-versus-host disease, systemic lupus erythematosus-related nephritis (13), 2,4,6-trinitrobenzene sulfonic acid-induced colitis (14), renal and cerebral ischemia (15)(16)(17)(18), and collagen-induced arthritis (19,20).…”

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confidence: 92%

TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

Salzmann

Lang

Rosenthal

et al. 2013

The Journal of Immunology

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We found recently that TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor–inducible-14 (Fn14) by virtue of their strong capability to reduce the freely available cytoplasmic pool of TNFR-associated factor (TRAF)2 and cellular inhibitors of apoptosis (cIAPs) antagonize the functions of these molecules in TNFR1 signaling, resulting in sensitization for apoptosis and inhibition of classical NF-κB signaling. In this study, we demonstrate that priming of cells with TWEAK also interferes with activation of the classical NF-κB pathway by CD40. Likewise, there was strong inhibition of CD40 ligand (CD40L)–induced activation of MAPKs in TWEAK-primed cells. FACS analysis and CD40L binding studies revealed unchanged CD40 expression and normal CD40L–CD40 interaction in TWEAK-primed cells. CD40L immunoprecipitates, however, showed severely reduced amounts of CD40 and CD40-associated proteins, indicating impaired formation or reduced stability of CD40L–CD40 signaling complexes. The previously described inhibitory effect of TWEAK on TNFR1 signaling has been traced back to reduced activity of the TNFR1-associated TRAF2–cIAP1/2 ubiquitinase complex and did not affect the stability of the immunoprecipitable TNFR1 receptor complex. Thus, the inhibitory effect of TWEAK on CD40 signaling must be based at least partly on other mechanisms. In line with this, signaling by the CD40-related TRAF2-interacting receptor TNFR2 was also attenuated but still immunoprecipitable in TWEAK-primed cells. Collectively, we show that Fn14 activation by soluble TWEAK impairs CD40L–CD40 signaling complex formation and inhibits CD40 signaling and thus identify the Fn14-TWEAK system as a potential novel regulator of CD40-related cellular functions.

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mentioning

confidence: 92%

TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

Salzmann

Lang

Rosenthal

et al. 2013

The Journal of Immunology

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“…Similar to its name-giving cousin TNF, it contributes to the development of autoinflammatory diseases in various experimental models, including collagen induced arthritis (9, 10), myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (11-13), 2,4,6-trinitrobenzenesulfonic acid-induced colitis (14,15), and systemic lupus erythematosus-related nephritis (16) and has also been implicated in atherosclerotic plaque progression in apolipoprotein E (apoE) knock-out mice (17,18). Furthermore, TWEAK and Fn14 play a role in detrimental inflammatory and fibrotic processes associated with the repair of injured tissue after liver damage, denervation, stroke, and renal and cerebral ischemia (19 -23).…”

Section: Tnf-like Weak Inducer Of Apoptosis (Tweak)mentioning

confidence: 99%

Fibroblast Growth Factor Inducible (Fn14)-specific Antibodies Concomitantly Display Signaling Pathway-specific Agonistic and Antagonistic Activity

Salzmann

Seher

Trebing

et al. 2013

Journal of Biological Chemistry

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Background: Fn14 is a therapeutic target in various diseases. Results: Anti-Fn14 antibodies activate the alternative NFB pathway but not other Fn14-related activities induced by soluble or membrane-bound TWEAK. Fc␥R-bound anti-Fn14 antibodies, however, activate the full spectrum of Fn14-associated activities. Conclusion: Anti-Fn14 antibodies elicit agonistic activities differing from those of the natural Fn14 ligand TWEAK. Significance: These findings influence the rationale of designing Fn14-targeted therapies.

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“…This cytokine acts on responsive cells via binding to the Fn14 (fibroblast growth factor-inducible 14) cell surface receptor, a 102-amino acid type I transmembrane protein originally described as a serum-and growth factor-inducible gene product in fibroblasts and smooth muscle cells (7)(8)(9). The TWEAK/Fn14 axis has been implicated in physiological wound repair and in the pathogenesis of ischemic stroke and several chronic inflammatory diseases (5,6), including rheumatoid arthritis (10,11) and inflammatory bowel disease (12).…”

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confidence: 99%

Full-length, Membrane-anchored TWEAK Can Function as a Juxtacrine Signaling Molecule and Activate the NF-κB Pathway

Brown

Ghosh

Winkles

2010

Journal of Biological Chemistry

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Tumor necrosis factor (TNF) family members are initially synthesized as type II transmembrane proteins, but some of these proteins are substrates for proteolytic enzymes that generate soluble cytokines with biological activity. TWEAK (TNFlike weak inducer of apoptosis), a member of the TNF family, is a multifunctional cytokine that acts via binding to a cell surface receptor named Fn14 (fibroblast growth factor-inducible 14). Studies conducted to date indicate that TWEAK-producing cells can co-express both membrane-anchored and soluble TWEAK isoforms, but there is little information on TWEAK proteolytic processing. Also, it is presently unclear whether membrane-anchored TWEAK, like soluble TWEAK, is biologically active. Here we show that full-length human TWEAK is processed intracellularly by the serine protease furin and identify TWEAK amino acid residues 90 -93 as the predominant furin recognition site. In addition, we report that full-length, membrane-anchored TWEAK can bind the Fn14 receptor on neighboring cells and activate the NF-B signaling pathway. Thus, TWEAK can act in a juxtacrine manner to initiate cellular responses, and this property may be important for TWEAK function during physiological wound repair and disease pathogenesis.TWEAK (tumor necrosis factor-like weak inducer of apoptosis) is a member of the TNF 2 superfamily of structurally related cytokines that together are involved in many critical biological processes, including development, organogenesis, tissue repair, and the innate and adaptive immune responses (1-3). TWEAK was initially described as a proapoptotic factor for certain tumor cell lines (4), but subsequent studies revealed that it can stimulate many other cellular responses, including cell proliferation, survival, and differentiation (5, 6). This cytokine acts on responsive cells via binding to the Fn14 (fibroblast growth factor-inducible 14) cell surface receptor, a 102-amino acid type I transmembrane protein originally described as a serum-and growth factor-inducible gene product in fibroblasts and smooth muscle cells (7-9). The TWEAK/Fn14 axis has been implicated in physiological wound repair and in the pathogenesis of ischemic stroke and several chronic inflammatory diseases (5, 6), including rheumatoid arthritis (10, 11) and inflammatory bowel disease (12).The human TWEAK gene encodes a 249-amino acid type II transmembrane protein, and when this full-length form of TWEAK was overexpressed in transfected HEK293-EBNA cells it was detected on the cell surface by FACS analysis, as expected (4). However, when a metabolic labeling and immunoprecipitation experiment was performed using the transfected cells, a smaller TWEAK form was found in conditioned medium (4). These results indicated that HEK293-EBNA cells could produce two TWEAK isoforms: a full-length, membraneanchored form and a smaller secreted form that is probably generated by TWEAK proteolytic processing. Subsequent studies have shown that other cell types can also co-express membrane-anchored and soluble TWEAK, indica...

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TWEAK/Fn14 Pathway: A Nonredundant Role in Intestinal Damage in Mice Through a TWEAK/Intestinal Epithelial Cell Axis

Cited by 65 publications

References 40 publications

TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

TWEAK Inhibits TRAF2-Mediated CD40 Signaling by Destabilization of CD40 Signaling Complexes

Fibroblast Growth Factor Inducible (Fn14)-specific Antibodies Concomitantly Display Signaling Pathway-specific Agonistic and Antagonistic Activity

Full-length, Membrane-anchored TWEAK Can Function as a Juxtacrine Signaling Molecule and Activate the NF-κB Pathway

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