TNF-related weak inducer of apoptosis receptor, a TNF receptor superfamily member, activates NF-κB through TNF receptor-associated factors

152

187

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.

Section: Discussionmentioning

confidence: 99%

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Campbell

Burkly

Gao

et al. 2006

152

187

“…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). Death signals initiated by Fn14 have been thoroughly studied in tumor cell lines and have been shown to involve caspase activation as well as cathepsin B-dependent necrosis (31).…”

Section: Discussionmentioning

confidence: 99%

“…DR3-independent signaling has been ascribed to a recently identified receptor for TWEAK, originally cloned as a mitogen-inducible gene in murine fibroblasts and named fibroblast growth factor-inducible 14 (Fn14) (27,28). Fn14 is distantly related to other members of the TNFR family and contains one cysteine-rich domain in the extracellular region and a TNFR-associated factor-binding domain in the cytoplasmic region (29,30). Despite its small size and the absence of a cytoplasmic death domain, Fn14 has been recently shown to mediate multiple pathways of TWEAK-induced cell death in transformed cells, including both caspase-dependent apoptosis and cathepsin Bdependent necrosis (31).…”

mentioning

confidence: 99%

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

Felli

Pedini

Zeuner

et al. 2005

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.

“…In contrast to all other TNFRs, having an ectodomain with two to six copies of a characteristic cystein-rich domain, Fn14 carries only one copy of this structural module (7,9). The cytoplasmic domain of Fn14 contains a TNFR-associated factor (TRAF) binding site allowing recruitment of the adapter proteins TRAF1, TRAF2, TRAF3, and TRAF5 that have also been implicated in signal transduction by most of the other TNFR family members (7,10,11). In particular, these molecules play a pivotal role in the activation of the classical and noncanonical NF-kB pathway, which can both be activated by TWEAK (10,12).…”

mentioning

confidence: 99%

Soluble and Transmembrane TNF-Like Weak Inducer of Apoptosis Differentially Activate the Classical and Noncanonical NF-κB Pathway

Roos

Wicovsky

Müller

et al. 2010

113