Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TNFSFS12)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101976

Synonyms

Historical Background

Tumor necrosis factor superfamily (TNFSF) members are implicated in numerous cellular processes such as proliferation, migration, inflammation, and cell death. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) was first identified as a novel member of the tumor necrosis factor superfamily of proteins displaying pro-apoptotic activity on interferon gamma (INF-γ)-treated human HT-29 colon carcinoma cells (Chicheportiche et al. 1997). The human TWEAK gene is located at chromosomal position 17p13.1 and encodes a 249-amino acid (aa) type II transmembrane-bound protein (mTWEAK). mTWEAK comprises an intracellular N-terminal domain, which contains a potential protein kinase C phosphorylation site, a transmembrane domain, and an extracellular TNF homology domain (THD) containing the receptor-binding site (Chicheportiche et al. 1997) (Fig. 1). mTWEAK is proteolytically processed by the serin protease furin, leading to the release of a 156-aa, 18 kDa soluble form (sTWEAK) (Chicheportiche et al. 1997). TWEAK sequence is highly conserved phylogenetically, showing 93% identity in the extracellular receptor-binding domain between mouse and human. This high level of identity is very unusual within the family and could indicate the importance of this protein. In 2001, Fn14 was identified as the functional TWEAK receptor using a cDNA expression library screening approach (Wiley et al. 2001). The human Fn14 gene is located at the chromosomal position 16p13.3 and encodes a 129-aa type I transmembrane protein of 14 kDa that is processed into a mature form of 102-aa (Wiley et al. 2001). The extracellular domain contains the ligand-binding site, and the intracellular domain contains a TNFR-associated factor (TRAF)-binding site implicated in signal transduction induced by TWEAK (Brown et al. 2003). Both TWEAK isoforms, mTWEAK and sTWEAK, bind to Fn14.
Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TNFSFS12), Fig. 1

TWEAK structure. The human TWEAK gene encodes a 249-amino acid (aa) type II transmembrane protein. TWEAK is defined by an extracellular conserved C-terminal trimerization domain, designated as TNF homology domain (THD). Soluble TWEAK (sTWEAK) can be released from the membrane-bound form (mTWEAK) by proteolytic cleavage in the stalk region by proteases (furin) as a 156-aa form. TWEAK exerts its activity by stimulation of Fn14 receptor

In 2007, Bover et al. reported a second potential TWEAK receptor, CD163 (Bover et al. 2007). CD163 is a hemoglobin scavenger receptor that is exclusively expressed by monocytes/macrophages (Kristiansen et al. 2001). It has been proposed that CD163 acts as a scavenger receptor for TWEAK, thus preventing TWEAK from exerting its biological actions by sequestering it from the environment. However, it has been reported that recombinant CD163 failed to decrease cell death induced by TWEAK in macrophages (Fick et al. 2012). The relevance of TWEAK/CD163 interaction must be confirmed, and more studies are needed in order to determine whether this interaction takes place either in vitro or in vivo.

TWEAK Expression and Functions

TNF-like weak inducer of apoptosis is expressed in several cell types and tissues including the intestine, pancreas, lung, brain, ovary, skeletal muscle, and vasculature and to a lesser degree in the kidney and liver (Burkly et al. 2007). Although TWEAK can be upregulated after injury, changes in TWEAK gene expression are usually moderated. By contrast, Fn14 expression in healthy tissues is usually low or undetectable, although it is rapidly and highly upregulated under pathological conditions as demonstrated in experimental models of chronic liver injury, myocardial infarction, colitis, denervation-induced skeletal muscle atrophy, restenosis after balloon injury, atherosclerosis, autoimmune encephalomyelitis, acute kidney injury, and cardiac dysfunction (Blanco-Colio 2014). Once Fn14 is upregulated, TWEAK binds and causes Fn14 trimerization and signal transduction. Although soluble TWEAK is responsible for the responses associated with Fn14, it has been recently reported that full-length, membrane-anchored TWEAK can, in a juxtacrine manner, bind to Fn14 on neighboring cells and activate the NF-kB signaling pathway, thus initiating the cellular response (Winkles 2008).

TWEAK protein can be upregulated by PMA and IFN-γ in cultured peripheral mononuclear cells and natural killer cells (Maecker et al. 2005). Fn14 trimerization induces the recruitment of TRAF2 and TRAF5 through its TRAF-binding motif (PIEET). This motif is responsible for activating different signaling pathways such as NF-κB and mitogen-activated protein kinases (MAPK) (Brown et al. 2003). Activation of NF-κB by TWEAK participates in the upregulation of several cytokines implicated in the recruitment of inflammatory cells within the injured tissue such as CCL2, CCL5, CCL19, and CCL21. TWEAK also activates MAPK, although activation of ERK, JNK, or p38 pathways is context dependent. MAPK activation has been reported in several cell lines, including Thp-1 monocytic cell line, endothelial cells, cardiomyocytes, fibroblast, and others (Winkles 2008). There are also different reports indicating that TWEAK activates PI3K/AKT in different cell types. TWEAK increases HMGB1 secretion by cultured monocytes through PI3K activation (Moreno et al. 2013). In addition, TWEAK also activates transforming growth factor-β-activated kinase 1 (TAK1), implicated in NF-κB and c-Jun N-terminal kinase (JNK)/AP-1 activation (Blanco-Colio 2014). Overall, TWEAK activates several signaling pathways that participate in the inflammatory response of the injured tissues (Fig. 2).
Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TNFSFS12), Fig. 2

The TWEAK/Fn14 signaling cascade. Binding of trimeric TWEAK to Fn14 receptor leads to the recruitment of TRAFs and cIAPs resulting in the activation of multiple downstream signaling cascades. TWEAK activates different MKKs, which phosphorylate ERK1/ERK2, JNK, ERK5, and p38MAPK resulting in the activation of downstream transcription factors such as SP-1 and AP-1. TWEAK stimulates both canonical (activation of TAK1) and noncanonical (activation of NIK) NF-kB pathways; in addition, TWEAK also activates JAK/STAT pathway. TWEAK TNF-like weak inducer of apoptosis, Fn14 fibroblast growth factor inducible 14, cIAP cellular inhibitor of apoptosis, TRAF TNF receptor-associated factor, TAK1 transforming growth factor β-activated kinase 1, TAB, TAK1-binding protein, IKK IκB kinase β, IκB inhibitor of nuclear factor of kappa B, NIK NF-κB-inducing kinase, MAPK mitogen-activated protein kinase, MKKs mitogen-activated protein kinase kinases, ERK extracellular signal-regulating kinase, JNK c-Jun N-terminal kinase, AP1 activator protein 1, SP1 specificity protein 1, JAK janus kinase, STAT signal transducer and activator of transcription

Biological Functions of TWEAK

Several functions with potential pathological significance have been related to TWEAK/Fn14 interaction and are dependent on the cell type, microenvironment, and cell activation. However, the basis for these differential responses is poorly understood. TWEAK can regulate cell proliferation, migration, differentiation, and death as well as tissue inflammation, angiogenesis, and regeneration (Chicheportiche et al. 1997; Winkles 2008). The precise role of TWEAK in different pathological situations needs to be characterized, since TWEAK has beneficial or deleterious effects depending on the stage of the disease (Burkly et al. 2007; Winkles 2008). TWEAK induces proliferation in several cell types, including epithelial, endothelial, vascular smooth muscle cells, tumor, and progenitor cells (Winkles 2008; Tarín et al. 2014). TWEAK also induces proliferation in vivo. Thus, gain- or loss-of-function experiments have demonstrated that TWEAK promotes proliferation in vascular smooth muscle cells (Tarín et al. 2014), renal tubular cells (Sanz et al. 2009), and liver progenitor cells (Tirnitz-Parker et al. 2010). There are different mechanisms implicated in cell proliferation induced by TWEAK including NF-kB activation, MKKs, and PI3K/Akt pathways. In fact, growth factors such as FGF-2 or VEGF induce endothelial cells proliferation via MKKs (Winkles 2008). The role of TWEAK in proliferation suggests that this protein may participate in tissue repair after injury and pathological hyperplasia.

TWEAK also participates in the inflammatory response observed after tissue injury. The ability of TWEAK to trigger chemokine production requires NF-κB activation and was originally described with tumor cells lines in vitro (Chicheportiche et al. 1997). After that, several studies have demonstrated that TWEAK induces production of chemokines, cytokines, and matrix metalloproteinases (MMPs) both in vitro and in vivo. In particular, TWEAK activates NF-κB in several cell types and increases the expression of pro-inflammatory proteins such as IL-6, IL-8, CCL2, and CCL5 in vascular smooth muscle cells, macrophages, human dermal fibroblast, and renal mesangial cells (Winkles 2008). In addition, TWEAK also increases the secretion of HMGB1 through NF-κB activation in human M1 macrophages (Moreno et al. 2013). HMGB1 is a DNA-binding cytokine that activates endothelial cells and monocytes/macrophages to express pro-inflammatory cytokines, chemokines, and adhesion molecules functioning as a critical mediator of inflammation. Exogenous administration of TWEAK increases chemokine expression and macrophages infiltration in atherosclerosis plaques and renal lesions (Muñoz-García et al. 2009). Furthermore, loss-of-function experiments have demonstrated that TWEAK deletion reduces pro-inflammatory chemokine expression in atherosclerotic lesions and abdominal aortic aneurysm (Sastre et al. 2014; Tarín et al. 2014). TWEAK injection also increases cytokine and chemokine secretion in kidneys (Sanz et al. 2014) and metalloproteinases expression and activation in damaged brain and aorta (Polavarapu et al. 2005; Tarín et al. 2014). Collectively, TWEAK induces pro-inflammatory activity on a broad spectrum of cells in vitro, though the fine pattern of activity may vary with the particular cell type.

Finally, TWEAK has been related with apoptosis of different cell types including neurons, tumor cell lines, monocytes, and renal and vascular cells, among others (Burkly et al. 2007). TWEAK-induced cell death is generally weak, requiring longer incubation times, high ligand concentration, and co-incubation with other sensitizing agents. The TWEAK receptor, Fn14, does not contain death domain in its cytoplasmic region as other members of the TNF superfamily. For this reason, the exact mechanism by which TWEAK induces cell death is not well known. These mechanisms included caspase-dependent and independent cell death and cathepsin B-dependent necrosis (Burkly et al. 2007). TWEAK can also modulate cell death in vivo. Blocking TWEAK signaling diminished cell death in animal models of cerebral ischemia, acute kidney injury, or abdominal aortic aneurysm.

TWEAK in Health and Diseases

TWEAK/Fn14 interaction induces pleiotropic actions that involve a response to tissue injury. After acute injury, Fn14 is upregulated and participates in acute inflammatory response and controls fibrogenic and angiogenic responses (Burkly et al. 2011). The beneficial role of TWEAK has been demonstrated in acute skeletal muscle, pancreatic, and liver injury (Burkly et al. 2011). Thus, inflammation and regeneration of acute injured skeletal muscle are delayed in Fn14-deficient mice. In addition, TWEAK increases inflammatory/fibrogenic responses and regeneration in acute liver injury. TWEAK also participates in regeneration after partial pancreatectomy. Fn14 plays a protective role during the acute stages of intestinal inflammation, and its absence promotes the development of colitis-associated cancer (Di Martino et al. 2016). Thus, TWEAK/Fn14 axis could participate in tissue healing after acute injury. In contrast, basic science studies using cells in culture, expression profiling studies using normal and diseased tissue specimens, and in vivo studies using wild-type (WT) or genetically engineered mice have all indicated that the TWEAK/Fn14 axis may play an important role in the pathophysiology of several different human diseases. In fact, gain- or loss-of-function experiments have revealed that TWEAK participates in renal, cardiovascular, and autoimmune diseases and cancer, among others. Thus, TWEAK induces different responses in kidney cells and on inflammatory cells during renal disease. In cultured murine tubular cells, TWEAK induces the expression of inflammatory cytokines, is mitogenic, and in the presence of sensitizing agents promotes apoptosis (Sanz et al. 2014). Similar actions were observed on glomerular mesangial cells. In addition, different animal models have demonstrated that TWEAK/Fn14 axis participates in acute and chronic kidney disease, non-compensatory renal growth, hyperlipidemic nephropathy, anti-GBM nephritis, and lupus nephritis (Sanz et al. 2014).

TWEAK is also involved in the pathological remodeling underlying cardiovascular disease (Blanco-Colio 2014). TWEAK is expressed in both the normal and pathological arterial wall, but Fn14 is almost absent in healthy arteries and its expression is highly upregulated in the carotid artery, femoral atherosclerotic plaques, and in abdominal aortic aneurysms. Binding of TWEAK to its receptor induces several responses in vascular and inflammatory cells. Thus, TWEAK increases adhesion molecules and pro-inflammatory cytokine expression in vascular cells and infiltrating macrophages, upregulates metaloproteinases activity, and participates in prothrombotic responses and vascular calcification (Sastre et al. 2014; Blanco-Colio 2014). Data from experimental models support that TWEAK and its functional receptor Fn14 are promising target for the treatment of patients with different CVD. Treatment with the TWEAK-neutralizing antibody or Fn14–Fc decoy protein has demonstrated a beneficial effect on the development and progression of atherosclerotic plaques in mice (Blanco-Colio 2014). Furthermore, Fn14 deletion or anti-TWEAK administration diminished the volume of the ischemic lesion after stroke (Blanco-Colio 2014). TWEAK/Fn14 may be also important in regulating myocardial structural remodeling and function and may play a role in the pathogenesis of dilated cardiomyopathy. In addition, TWEAK aggravates left ventricular dysfunction after myocardial infarction in mice (Jarr et al. 2014).

Finally, both TWEAK and Fn14 expression have been detected in tumors, and TWEAK/Fn14 signaling may promote tumor growth in vivo through a variety of mechanisms such as active proliferation, invasion, angiogenesis, and inflammation (Burkly et al. 2007; Winkles 2008). High expression of Fn14 has been shown in several tumor types, including colorectal cancer, pancreatic carcinoma, non-small cell lung cancer (NSCLC), and ovarian cancer. Moreover, Fn14 expression is considered a negative prognostic factor in glioblastoma, breast cancer, gastric cancer, and NSCLC.

The abovementioned animal studies support the contention that TWEAK-neutralizing agents could be effective therapeutics for different diseases. In fact, phase I and II studies with anti-TWEAK-neutralizing antibodies have been done. A phase I clinical trial tested the TWEAK-blocking antibody BIIB023 in patients with rheumatoid arthritis (RA) (Wisniacki et al. 2013), being BIIB 23 well tolerated during the follow-up. This antibody is currently under a phase II trial in patients with lupus nephritis. In addition, in a phase I trial, RG7212 (anti-TWEAK-neutralizing antibody) has demonstrated efficacy in patients with advanced solid tumors (Meulendijks et al. 2016). All together, these studies have demonstrated good tolerability to anti-TWEAK treatment in humans and indicate that TWEAK could be a new target for the treatment of cancer and/or inflammatory diseases.

Soluble TWEAK as a Biomarker of Cardiovascular Diseases

As commented above, TWEAK can be proteolytically processed and secreted as a soluble form. Among the different proteins that could be differentially secreted by the pathological arterial wall, sTWEAK was identified as a protein that is released in lower amount by carotid atherosclerotic plaques compared with healthy arteries (Blanco-Colio et al. 2007). After that, the association of sTWEAK with CVD or CVD-related diseases has been extensively studied. sTWEAK concentrations are diminished in patients with coronary artery disease, abdominal aortic aneurysm, systolic heart failure, type 2 diabetes, and chronic kidney disease (CKD) (Blanco-Colio 2014). In addition, sTWEAK was an independent predictor of both cardiovascular mortality and first cardiovascular events in CKD patients (Fernández-Laso et al. 2016). Overall, all these data indicate that sTWEAK could be a novel biomarker for diagnostic and prognostic of CVD. However, more large-scale studies to consolidate its usefulness are required.

Conclusion

Acute tissue injury triggers a well-orchestrated tissue repair response. However, chronic tissue injury is characterized by dysregulated and unresolved wound healing processes, including pro-inflammatory mediator and growth factor expression, immune cell infiltration, and angiogenesis. TWEAK has emerged as a key cytokine that regulates tissue response to injury and participates in pathological tissue damage.

Summary

TWEAK is a cytokine of the TNF superfamily that induces, through its sole receptor Fn14, different cellular responses such as cell proliferation, migration, differentiation, death, and inflammation. TWEAK activates several signal pathways including canonical and noncanonical NF-kB activation, MAPKs, PI3K/Akt, and JAK/STAT pathways. TWEAK is expressed in both normal and pathological tissues. However, the expression of Fn14 is absent or low in normal tissues but is highly upregulated after injury. Gain- or loss-of-function experiments in animal models indicate that TWEAK is implicated in promoting acute and chronic disease including renal, autoimmune, and cardiovascular diseases as well as cancer. TWEAK-neutralizing agents could be effective therapeutics for different diseases, and different clinical trials are ongoing.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Vascular Research LabFIIS-Fundación Jiménez DíazMadridSpain
  2. 2.Biomedical Research Center in Cardiovascular MedicineCIBERCVSpain