TWEAK Mediates Signal Transduction and Differentiation of RAW264.7 Cells in the Absence of Fn14/TweakR

Polek, Tara C.; Talpaz, Moshe; Darnay, Bryant G.; Spivak-Kroizman, Taly R.

doi:10.1074/jbc.m302518200

Cited by 138 publications

(118 citation statements)

References 36 publications

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“…Polek et al (46) reported that TWEAK can induce differentiation into osteoclasts of RAW cells that reportedly do not display the Fn14 receptor. As no other TWEAK receptor has been demonstrated to date, this observation may be explained by the recent finding by De Ketelaere et al (47) that soluble TWEAK can internalize into several cell lines (not via Fn14) and translocate directly to the nucleus, leading to nuclear translocation of GSK-3␤ and p65 and induction of NF-B-driven gene expression.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Campbell

Burkly

Gao

et al. 2006

The Journal of Immunology

152

187

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TNF-like weak inducer of apoptosis, or TWEAK, is a relatively new member of the TNF-ligand superfamily. Ligation of the TWEAK receptor Fn14 by TWEAK has proinflammatory effects on fibroblasts, synoviocytes, and endothelial cells. Several of the TWEAK-inducible cytokines are important in the pathogenesis of kidney diseases; however, whether TWEAK can induce a proinflammatory effect on kidney cells is not known. We found that murine mesangial cells express cell surface TWEAK receptor. TWEAK stimulation of mesangial cells led to a dose-dependent increase in CCL2/MCP-1, CCL5/RANTES, CXCL10/IFN-γ-induced protein 10 kDa, and CXCL1/KC. The induced levels of chemokines were comparable to those found following mesangial cell exposure to potent proinflammatory stimuli such as TNF-α + IL-1β. CXCL11/interferon-inducible T cell α chemoattractant, CXCR5, mucosal addressin cell adhesion molecule-1, and VCAM-1 were up-regulated by TWEAK as well. TWEAK stimulation of mesangial cells resulted in an increase in phosphorylated Iκ-B, while pretreatment with an Iκ-B phosphorylation inhibitor significantly blocked chemokine induction, implicating activation of the NF-κB signaling pathway in TWEAK-induced chemokine secretion. Importantly, the Fn14-mediated proinflammatory effects of TWEAK on kidney cells were confirmed using mesangial cells derived from Fn14-deficient mice and by injection in vivo of TWEAK into wild-type vs Fn14-deficient mice. Finally, TWEAK-induced chemokine secretion was prevented by treatment with novel murine anti-TWEAK Abs. We conclude that TWEAK induces mesangial cells to secrete proinflammatory chemokines, suggesting a prominent role for TWEAK in the pathogenesis of renal injury. Our results support Ab inhibition of TWEAK as a potential new approach for the treatment of chemokine-dependent inflammatory kidney diseases.

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Section: Discussionmentioning

confidence: 99%

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Campbell

Burkly

Gao

et al. 2006

The Journal of Immunology

152

187

View full text Add to dashboard Cite

show abstract

“…For example, whereas both soluble TWEAK and memTWEAK are strong stimuli of the alternative NF-kB pathway, only memTWEAK also efficiently triggers the classical NF-kB pathway (24). Several members of the TNFR-associated factor (TRAF) family and Rac1 have been identified as Fn14-interacting molecules, but their relevance for defined aspects of Fn14 signal transduction is poorly understood (25)(26)(27). In molecular terms the best elucidated Fn14 signaling event is presumably TRAF2 recruitment and its relevance for alternative NFkB signaling (28).…”

mentioning

confidence: 99%

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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“…TWEAK is widely expressed in many tissues including heart, skeletal muscle, and kidney (11,14). Binding of TWEAK to its receptor, Fn14 (13), mediates multiple biologic effects such as cellular growth, proliferation, and migration; osteoclastogenesis; angiogenesis; and apoptosis (15)(16)(17). sTWEAK plasma levels decrease with impaired renal function and associate with the aggravation of the endothelial function and the mortality risk (18,19).…”

mentioning

confidence: 99%

Combined Therapy with Renin-Angiotensin System and Calcium Channel Blockers in Type 2 Diabetic Hypertensive Patients with Proteinuria

Yılmaz¹,

Carrero²,

Martı́n-Ventura³

et al. 2010

Clinical Journal of the American Society of Nephrology

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Results: All treatment strategies effectively increased FMD and reduced proteinuria, confirming a more prone reduction with the combined therapy. These improvements were followed by significant PTX3 reductions. Valsartan alone and in combination with amlodipine achieved significant incremental raises in sTWEAK plasma levels. More importantly, the changes observed in sTWEAK (␤ ‫؍‬ 0.25, P ‫؍‬ 0.006) or PTX3 (␤ ‫؍‬ ؊0.24, P ‫؍‬ 0.007) plasma levels were independently associated with the improvement in ultrasonographically measured FMD.Conclusions: This study shows that treatment with antihypertensive drugs improves FMD and normalizes proteinuria, PTX3, and sTWEAK in diabetic CKD stage I patients with hypertension. The improvement in FMD was independently associated with PTX3 and sTWEAK normalization. Two surrogate biomarkers of endothelial function are therefore identified with potential as therapeutic targets. The study was registered in clinicaltrials.gov as NCT00921570.

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TWEAK Mediates Signal Transduction and Differentiation of RAW264.7 Cells in the Absence of Fn14/TweakR

Abstract: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor family that is implicated in apoptosis, proliferation, migration, and inflammation. We describe our findings showing that TWEAK mediated the differentiation of RAW264.

Cited by 138 publications

References 36 publications

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

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

Combined Therapy with Renin-Angiotensin System and Calcium Channel Blockers in Type 2 Diabetic Hypertensive Patients with Proteinuria

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