Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Campbell, Sammy C.; Burkly, Linda C.; Gao, Hua; Berman, Joan W.; Su, Lihe; Browning, Beth; Zheng, Timothy S.; Schiffer, Lena; Michaelson, Jennifer S.; Putterman, Chaim

doi:10.4049/jimmunol.176.3.1889

Cited by 152 publications

(193 citation statements)

References 48 publications

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“…In contrast, the only TNF family members that have been implicated in CXCL10 expression are TNF-a (44), CD40L (45,46). and TWEAK (47), all in nonlymphoid cell types. The finding that a T cell costimulatory receptor induces chemokine expression during priming is novel and begs for a conceptual interpretation.…”

Section: Discussionmentioning

confidence: 99%

CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool

Peperzak

Veraar

Xiao

et al. 2013

The Journal of Immunology

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Various cell types can produce the chemokine CXCL10 in response to IFN-γ stimulation. CXCL10 is generally viewed as a proinflammatory chemokine that promotes recruitment of CD8+ and Th1-type CD4+ effector T cells to infected or inflamed nonlymphoid tissues. We show that CXCL10 plays a role during CD8+ T cell priming in the mouse. Genome-wide expression profiling revealed the Cxcl10 gene as a target of CD27/CD70 costimulation in newly activated CD8+ T cells. CD27/CD70 costimulation is known to promote activated T cell survival, but CXCL10 did not affect survival or proliferation of primed CD8+ T cells in vitro. Accordingly, CXCL10 could not fully rescue CD27 deficiency in mice infected with influenza virus. Rather, CXCL10 acted as chemoattractant for other activated CD8+ T cells. It signaled downstream of CD27 in a paracrine fashion to promote generation of the CD8+ effector T cell pool in the Ag-draining lymph nodes. Consistently, CD8+ T cells required expression of the CXCL10 receptor CXCR3 for their clonal expansion in a CD27/CD70-dependent peptide-immunization model. Our findings indicate that CXCL10, produced by primed CD8+ T cells in response to CD27/CD70 costimulation, signals to other primed CD8+ T cells in the lymph node microenvironment to facilitate their participation in the CD8+ effector T cell pool.

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Section: Discussionmentioning

confidence: 99%

CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool

Peperzak

Veraar

Xiao

et al. 2013

The Journal of Immunology

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“…Thus, TWEAK regulation of vastly different cellular responses is probably due, at least in part, to cell type-specific differences in Fn14-mediated intracellular signalling events. 72 reported that intravenous TWEAK injection (200 µg) induces MCP1 and IP10 mRNA expression in kidney. This geneexpression data, in combination with additional findings demonstrating that anti-TWEAK neutralizing monoclonal antibodies reduce inflammatory cell infiltration in mouse models of rheumatoid arthritis47 , 83 and multiple sclerosis 85 (see below) and that Fn14-null mice display a deficient inflammatory response following tissue injury 31 , is consistent with the proposal that TWEAK is in fact a pro-inflammatory cytokine.…”

Section: Tweak-dependent Fn14 Signallingmentioning

confidence: 99%

The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

Winkles

2008

Nat Rev Drug Discov

515

662

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TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. TWEAK acts by binding to Fn14, a highly inducible cell-surface receptor that is linked to several intracellular signalling pathways, including the nuclear factor-κB (NF-κB) pathway. The TWEAK-Fn14 axis normally regulates various physiological processes, in particular it seems to play an important, beneficial role in tissue repair following acute injury. Furthermore, recent studies have indicated that TWEAK-Fn14 axis signalling may contribute to cancer, chronic autoimmune diseases and acute ischaemic stroke. This Review provides an overview of TWEAK-Fn14 axis biology and summarizes the available data supporting the proposal that both TWEAK and Fn14 should be considered as potential targets for the development of novel therapeutics.Cytokines are a large and diverse group of plasma-membrane-associated or secreted proteins that bind cell-surface receptors and thereby regulate many important biological processes. These processes include development, haematopoesis, inflammation, immune responses and tissue repair1. The tumour necrosis factor (TNF) ligand superfamily, and the receptors that mediate their effects, is a cytokine-receptor subgroup that has attracted considerable interest as a potential source of therapeutic targets for the management of complex human diseases. TNF superfamily ligands are primarily expressed as type II transmembrane proteins, but in some cases they are processed into smaller, secreted proteins that retain biological activity2 , 3. Both the anchored and soluble cytokines contain a C-terminal TNF homology domain that mediates self-trimerization and receptor binding. TNF superfamily members bind to one or more members of the TNF receptor (TNFR) superfamily, most of which are type I or type III transmembrane proteins2 , 3. These receptors are characterized by the presence of an extracellular, ligand-binding region containing one to four cysteine-rich domains and a cytoplasmic tail containing one or more adaptor-protein binding sites. TWEAK (also known as TNFSF12, APO3L, CD255) and its cognate receptor Fn14 (also known as TNFRSF12A, TWEAKR, CD266) are members of the TNF and TNFR superfamilies, respectively, and the discovery of this cytokine-receptor axis was in itself an interesting scientific journey. In 1997, Chicheportiche et al. 4 reported the identification of a novel TNF-like protein that had pro-apoptotic activity on interferon-α (IFN-γ)-treated human HT-29 colon carcinoma cells. Consequently, they named this cytokine TNF-like weak inducer of apoptosis (abbreviated to TWEAK). These investigators were recipients of unexpected good fortune, as they were not originally aiming to identify new TNF superfamily members; indeed, the TWEAK cDNA was cloned during a screen for erythropoietin-related mRNAs in mouse macrophages. In 1998, Marsters et al. 5 reported the identification of the same protein by searching an expre...

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“…Besides inducing proinflammatory cytokines and chemokines, TWEAK can also affect cell proliferation and survival (13,14,26). As both kidney cell proliferation and apoptosis have been described in LN (27)(28)(29), we assessed renal cell proliferation and apoptosis by Ki-67 and caspase 3 staining, respectively.…”

Section: Fn14-deficient Mice Have Reduced Renal Igg Deposition Cytokmentioning

confidence: 99%

“…Recently, we have shown that Fn14 is expressed by murine kidney mesangial cells and podocytes, and that TWEAK stimulates mesangial cells to secrete high levels of potent proinflammatory chemokines including MCP-1, RANTES, IP-10, and KC (13). Justo et al (14) reported that renal tubular cells display Fn14 as well.…”

mentioning

confidence: 99%

TWEAK/Fn14 Interactions Are Instrumental in the Pathogenesis of Nephritis in the Chronic Graft-versus-Host Model of Systemic Lupus erythematosus

Zhao

Burkly

Campbell

et al. 2007

The Journal of Immunology

Self Cite

143

144

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TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a prominent inducer of proinflammatory cytokines in vitro and in vivo. We previously found that kidney cells display the TWEAK receptor Fn14, and that TWEAK stimulation of mesangial cells and podocytes induces a potent proinflammatory response. Several of the cytokines up-regulated in the kidney in response to TWEAK are instrumental in Lupus nephritis; we therefore hypothesized that TWEAK/Fn14 interactions may be important in the cascade(s) leading to renal damage in systemic Lupus erythematosus. In this study, we analyzed the effects of Fn14 deficiency in the chronic graft-vs-host model of SLE, and the benefits of treatment with an anti-TWEAK mAb in this mouse model. We found that anti-nuclear Ab titers were no different between C57BL/6 Fn14 wild-type and deficient mice injected with alloreactive bm12 splenocytes. However, kidney disease was significantly less severe in Fn14 knockout mice. Furthermore, kidney IgG deposition, IL-6, MCP-1, RANTES, and IP-10, as well as macrophage infiltration, were significantly decreased in Fn14-deficient mice with induced lupus. Similarly, mice with induced Lupus treated with an anti-TWEAK neutralizing mAb had significantly diminished kidney expression of IL-6, MCP-1, IL-10, as well as proteinuria, but similar autoantibody titers, as compared with control-treated mice. We conclude that TWEAK is an important mediator of kidney damage that acts by promoting local inflammatory events, but without impacting adaptive immunity in this experimental LN model. Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE.

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Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Cited by 152 publications

References 48 publications

CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool

CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool

The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

TWEAK/Fn14 Interactions Are Instrumental in the Pathogenesis of Nephritis in the Chronic Graft-versus-Host Model of Systemic Lupus erythematosus

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