Search

TWEAK (tumor necrosis factor-like weak inducer of apoptosis) is a member of the TNF superfamily that controls a multitude of cellular events including proliferation, migration, differentiation, apoptosis, angiogenesis, and inflammation. TWEAK control of these events is via an expanding list of intracellular signalling pathways which include NF-κB, ERK/MAPK, Notch, EGFR and AP-1. Two receptors have been identified for TWEAK – Fn14, which targets the membrane bound form of TWEAK, and CD163, which scavenges the soluble form of TWEAK. TWEAK appears to elicit specific events based on the receptor to which it binds, tissue type in which it is expressed, specific extrinsic conditions, and the presence of other cytokines. TWEAK signalling is protective in healthy tissues, but in chronic inflammatory states become detrimental to the tissue. Consistent data show a role for the TWEAK/FN14/CD163 axis in metabolic disease, chronic autoimmune diseases, and acute ischaemic stroke. Low circulating concentrations of soluble TWEAK are predictive of poor cardiovascular outcomes in those with and without diabetes. This review details the current understanding of the TWEAK/Fn14/CD163 axis as one of the chief regulators of immune signalling and its cell-specific role in metabolic disease development and progression. [ABSTRACT FROM AUTHOR]

Background and aim: As a proinflammatory cytokine, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in the progression of renal fibrosis by binding to its receptor, fibroblast growth factor-inducible 14 (Fn14). However, the effect of Fn14 inhibition on tubular epithelial cell-mediated tubulointerstitial fibrosis remains unclear. This study aimed to elucidate the role of TWEAK/Fn14 interaction in the development of experimental tubulointerstitial fibrosis as well as the protective effect of Fn14 knockdown on proximal tubular epithelial cells. Methods: A murine model of unilateral ureteral obstruction was constructed in both wild-type and Fn14-deficient BALB/c mice, followed by observation of the tubulointerstitial pathologies. Results: Fn14 deficiency ameliorated the pathological changes, including inflammatory cell infiltration and cell proliferation, accompanied by reduced production of profibrotic factors and extracellular matrix deposition. In vitro experiments showed that TWEAK dose-dependently enhanced the expression of collagen I, fibronectin, and α-smooth muscle actin in proximal tubular epithelial cells. Interestingly, TWEAK also upregulated the expression levels of Notch1/Jagged1. Fn14 knockdown and Notch1/Jagged1 inhibition also mitigated the effect of TWEAK on these cells. Conclusions: In conclusion, TWEAK/Fn14 signals contributed to tubulointerstitial fibrosis by acting on proximal tubular epithelial cells. Fn14 inhibition might be a therapeutic strategy for protecting against renal interstitial fibrosis. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor-inducible-14 (Fn14), a receptor for tumor necrosis-like weak inducer of apoptosis, is expressed in the neurons of dorsal root ganglion (DRG). Its mRNA is increased in the injured DRG following peripheral nerve injury. Whether this increase contributes to neuropathic pain is unknown. We reported here that peripheral nerve injury caused by spinal nerve ligation (SNL) increased the expression of Fn14 at both protein and mRNA levels in the injured DRG. Blocking this increase attenuated the development of SNL-induced mechanical, thermal, and cold pain hypersensitivities. Conversely, mimicking this increase produced the increases in the levels of phosphorylated extracellular signal-regulated kinase ½ and glial fibrillary acidic protein in ipsilateral dorsal horn and the enhanced responses to mechanical, thermal, and cold stimuli in the absence of SNL. Mechanistically, the increased Fn14 activated the NF-κB pathway through promoting the translocation of p65 into the nucleus of the injured DRG neurons. Our findings suggest that Fn14 may be a potential target for the therapeutic treatment of peripheral neuropathic pain. [ABSTRACT FROM AUTHOR]

Introduction: Physical health and function depend upon both genetic inheritance and environmental factors (e.g., exercise training).Purpose: To enhance the understanding of heritability/adaptability, we explored the skeletal muscle health and physiological performance of monozygotic (MZ) twins with > 30 years of chronic endurance training vs. no specific/consistent exercise.Methods: One pair of male MZ twins (age = 52 years; Trained Twin, TT; Untrained Twin, UT) underwent analyses of: (1) anthropometric characteristics and blood profiles, (2) markers of cardiovascular and pulmonary health, and (3) skeletal muscle size, strength, and power and molecular markers of muscle health.Results: This case study represents the most comprehensive physiological comparison of MZ twins with this length and magnitude of differing exercise history. TT exhibited: (1) lower body mass, body fat%, resting heart rate, blood pressure, cholesterol, triglycerides, and plasma glucose, (2) greater relative cycling power, anaerobic endurance, and aerobic capacity (VO2max), but lower muscle size/strength and poorer muscle quality, (3) more MHC I (slow-twitch) and fewer MHC IIa (fast-twitch) fibers, (4) greater AMPK protein expression, and (5) greater PAX7, IGF1Ec, IGF1Ea, and FN14 mRNA expression than UT.Conclusions: Several measured differences are the largest reported between MZ twins (TT expressed 55% more MHC I fibers, 12.4 ml/kg/min greater VO2max, and 8.6% lower body fat% vs. UT). These data collectively (a) support utilizing chronic endurance training to improve body composition and cardiovascular health and (b) suggest the cardiovascular and skeletal muscle systems exhibit greater plasticity than previously thought, further highlighting the importance of studying MZ twins with large (long-term) differences in exposomes. [ABSTRACT FROM AUTHOR]

The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H gliomas exhibit low Fn14 mRNA and protein levels compared to IDH1 WT gliomas. Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2′-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation. [ABSTRACT FROM AUTHOR]

The aim of our research is to investigate the regulatory role of TNF-like weak inducer of apoptosis- fibroblast growth factor-inducible 14 (TWEAK-Fn14) pathway in nuclear factor-kappa B (NF-κB) expression and neurogenesis status after spinal cord injury (SCI). We constructed a mice model of spinal cord injury and injected different lentiviral vectors which were transfected with TWEAK, TWEAK small interfering RNA (siRNA) and Fn14 siRNA into different groups of mice. Locomotor functional recovery status of the hind limb in mice was assessed using the Basso, Beattie and Bresnahan (BBB) test. Apoptosis status in the injured area was examined via TDT-mediated dUTP-biotin nick end-labeling (TUNEL) staining, the expression of GAP-43 in injured spinal cord was quantified by immunohistochemistry and expressions of TWEAK, Fn14, NF-κB, TNF-α, and IL-1β were evaluated by either western blot or ELISA. The expressions of TWEAK, Fn14, and NF-κB in the model group were significantly higher compared with those in the control group. Furthermore, the TWEAK group in which TWEAK was overexpressed exhibited significantly higher expressions of TWEAK, Fn14, and NF-κB, TNF-α and IL-1β in relation to those in the model group ( P < 0.05 for all). Moreover, the transfection of Fn14 siRNA antagonized the above effect of TWEAK transfection on injured mice. On the other hand, the TWEAK siRNA group in which the expression of TWEAK was inhibited exhibited significantly lower expressions of TWEAK, Fn14, NF-κB, TNF-α, and IL-1β ( P < 0.05 for all). Moreover, the transfection of TWEAK siRNA enhanced the locomotor functional recovery status in injured mice and suppressed the apoptosis of injured areas ( P < 0.05 for all). In conclusion, stimulating the TWEAK-Fn14 pathway may elevate the expression of NF-κB, thereby slow the function recovery of SCI mice whereas inhibiting the TWEAK-Fn14 pathway may improve the neurogenesis status in mice with spinal cord injuries. [ABSTRACT FROM AUTHOR]

TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNFSF ligands, initially synthesized as a type II transmembrane protein. TWEAK signaling occurs via binding to Fn14, a type I transmembrane receptor belonging to the TNF receptor superfamily. TWEAK/Fn14 activation controls several cellular responses, including proliferation, angiogenesis, induction of inflammatory cytokines. Studies have indicated that expression of TWEAK/Fn14 was dysregulated in autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease. Functional analysis suggested that TWEAK/Fn14 may play an important role in the development of these diseases. In this review, we discuss the TWEAK/Fn14 pathway and its significant role in autoimmune disorders. The information obtained may lead to a better understanding of the insights into TWEAK/Fn14 in these autoimmune diseases. [ABSTRACT FROM AUTHOR]

The five-year survival rate in advanced non-small cell lung cancer (NSCLC) remains below ten percent. The invasive and metastatic nature of NSCLC tumor cells contributes to the high mortality rate, and as such the mechanisms that govern NSCLC metastasis is an active area of investigation. Two surface receptors that influence NSCLC invasion and metastasis are the hepatocyte growth factor receptor (HGFR/MET) and fibroblast growth factor-inducible 14 (FN14). MET protein is over-expressed in NSCLC tumors and associated with poor clinical outcome and metastasis. FN14 protein is also elevated in NSCLC tumors and positively correlates with tumor cell migration and invasion. In this report, we show that MET and FN14 protein expressions are significantly correlated in human primary NSCLC tumors, and the protein levels of MET and FN14 are elevated in metastatic lesions relative to patient-matched primary tumors. In vitro, HGF/MET activation significantly enhances FN14 mRNA and protein expression. Importantly, depletion of FN14 is sufficient to inhibit MET-driven NSCLC tumor cell migration and invasion in vitro. This work suggests that MET and FN14 protein expressions are associated with the invasive and metastatic potential of NSCLC. Receptor-targeted therapeutics for both MET and FN14 are in clinical development, the use of which may mitigate the metastatic potential of NSCLC. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF super family that controls many cellular activities including proliferation, migration, differentiation, apoptosis, and inflammation by binding to fibroblast growth factor-inducible 14 (Fn14), a highly inducible cell surface receptor. Recent studies have indicated that TWEAK-Fn14 axis signaling may contribute to chronic autoimmune diseases. TWEAK expression via microglia in cortical lesions, presence of TWEAK macrophages in inflamed leptomeninges, and absence of TWEAK/Fn14 expression in healthy brain implicates importance of this pathway in pathogenesis of multiple sclerosis lesions. TWEAK-Fn14 axis blockade has also shown promise in various multiple sclerosis animal models. Stimulation of the TWEAK/Fn14 pathway can result in activation of both canonical and noncanonical NF-κB signaling and could also stimulate mitogen-activated protein kinase (MAPK) signaling pathways. Here, we have reviewed evidence of the possible role of TWEAK-Fn14 axis in pathophysiology of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) via neuroinflammation, tissue remodeling, blood-brain barrier (BBB) disruption, neurodegeneration, and astrogliosis. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a fatal disease for which no cure is yet available. The leading cause of death in PAH is right ventricular (RV) failure. Previously, the TNF receptor superfamily member fibroblast growth factor-inducible molecule 14 (Fn14) has been associated with different fibrotic diseases. However, so far there is no study demonstrating a causal role for endogenous Fn14 signaling in RV or LV heart disease. The purpose of this study was to determine whether global ablation of Fn14 prevents RV fibrosis and remodeling improving heart function. Here, we provide evidence for a causative role of Fn14 in pulmonary artery banding (PAB)-induced RV fibrosis and dysfunction in mice. Fn14 expression was increased in the RV after PAB. Mice lacking Fn14 (Fn14) displayed substantially reduced RV fibrosis and dysfunction following PAB compared to wild-type littermates. Cell culture experiments demonstrated that activation of Fn14 induces collagen expression via RhoA-dependent nuclear translocation of myocardin-related transcription factor-A (MRTF-A)/MAL. Furthermore, activation of Fn14 in vitro caused fibroblast proliferation and myofibroblast differentiation, which corresponds to suppression of PAB-induced RV fibrosis in Fn14 mice. Moreover, our findings suggest that Fn14 expression is regulated by endothelin-1 (ET-1) in cardiac fibroblasts. We conclude that Fn14 is an endogenous key regulator in cardiac fibrosis and suggest this receptor as potential new target for therapeutic interventions in heart failure. [ABSTRACT FROM AUTHOR]

Background: The receptor for the cytokine TWEAK (TweakR) is a cell surface member of the tumor necrosis factor receptor superfamily with diverse biological roles. TNFRSF family members are appealing therapeutic targets in oncology due to their aberrant expression and function in tumor cells. The goal of the current study was to examine the potential of TweakR as a therapeutic target in breast cancer. Methods: Expression of TweakR in primary breast cancer tissues and metastases was characterized using immunohistochemistry. To determine the functional relevance of TweakR, breast cancer cell lines were treated in vitro and in vivo with enavatuzumab, a humanized mAb against TweakR. Results: Overexpression of TweakR was observed in infiltrating tumors compared to normal adjacent breast tissues, and strong staining of TweakR was observed in all subtypes of invasive ductal breast cancer. In addition, a positive correlation of TweakR and HER2 expression and co-localization were observed, irrespective of ER status. TweakR expression was also observed in bone metastasis samples from primary breast cancer but rarely in benign tumors. Enavatuzumab inhibited the in vitro growth of TweakR-expressing breast cancer cell lines, and this activity was augmented by cross-linking the mAb. In addition, enavatuzumab significantly inhibited the in vivo growth of multiple breast cancer xenograft models including a model of metastasis. Conclusions: TweakR is highly expressed in all subtypes of invasive ductal breast cancer, and enavatuzumab administration exhibited a dose-dependent inhibition of primary tumor growth and lung metastasis and enhanced the antitumor activity of several chemotherapy agents currently used to treat breast cancer. These data provide the rationale to evaluate enavatuzumab as a potential therapy for the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

The pathophysiological basis of heart failure is cardiac remodeling, a process that comprises structural and functional changes including cardiomyocyte proliferation, hypertrophy, necrosis, apoptosis, autophagy, interstitial fibrosis, contractile dysfunction and ventricular dilatation. Accumulating evidence demonstrate that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is involved in the process by binding its receptor fibroblast growth factor-inducible molecule 14 (Fn14). In this review, we will discuss the potential role of the TWEAK/Fn14 axis in cardiac remodeling, elucidate its possible mechanisms and explore new therapeutic targets for heart failure. [ABSTRACT FROM AUTHOR]

We wished to elucidate a potential role of the tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible molecule 14 (Fn14) axis in myocardial fibrosis. Stimulation of neonatal rat cardiac fibroblasts (CFs) with TWEAK could increase CFs numbers and collagen synthesis. Conversely, when CFs were pretreated with siRNA against Fn14, induction of cell proliferation and collagen synthesis by TWEAK were inhibited. Pretreatment with TWEAK on CFs induced activation of the nuclear factor-kappaB (NF-кB) pathway and subsequently increased the production of metalloproteinase-9 (MMP-9). Cell treatment with siRNA against Fn14 led to inhibition of the NF-кB pathway. Additionally, after stimulation of cell with ammonium pyrrolidine dithiocarbamate, cell proliferation and collagen synthesis induced by NF-кB and the upregulation of MMP-9 production were inhibited. The present study suggested that the TWEAK/Fn14 axis increased cell proliferation and collagen synthesis by activating the NF-кB pathway and increasing MMP-9 activity. This axis may be important for regulating myocardial fibrosis. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a recently identified proinflammatory cytokine of the TNF superfamily. Through activation of the fibroblast growth factor-inducible 14 (Fn14) receptor, TWEAK regulates cell proliferation, cell death and inflammation. The available evidences have indicated that TWEAK might be a target for therapeutic intervention in renal, vascular injury and neuropathy. Since renal, vascular and neuropsychiatric complications are frequently encountered in systemic lupus erythematosus (SLE)-a systemic autoimmune disease, TWEAK-Fn14 pathway may be implicated in the pathogenesis of SLE. In this review, we will discuss the TWEAK-Fn14 pathway and the therapeutic potential of modulating this pathway in SLE. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines, including TNF family members, have been shown to play a critical role in cardiac remodeling. FGF-inducible 14-kDa protein (Fn14, TNFrsf12a or TWEAKR) is the smallest member of the TNF-receptor family. Currently, little is known about the functional role of Fn14 and its only known ligand TNF-like weak inducer of apoptosis (TWEAK) in the heart. We therefore evaluated the expression and regulation of Fn14 in cardiomyocytes and in experimental myocardial infarction. In order to study the regulation of Fn14, myocardial infarction was induced in CD-1 mice and neonatal rat cardiomyocytes were used for in vitro studies. TWEAK and Fn14 were markedly upregulated in the remodeling myocardium after experimental myocardial infarction in vivo. Likewise, fibroblast growth factor 1, norepinephrine and angiotensin II as well as mechanical stretch were able to strongly induce Fn14 expression in cardiomyocytes. This induction is mediated via the Rho/ROCK pathway, since the known inhibitors C3 exoenzyme for RhoA and Y27632 for ROCK prevented the upregulation of Fn14 in cardiomyocytes. Consistently, pretreatment of cardiomyocytes with siRNA against Rho A and ROCK also abolished Fn14 induction. Moreover, stimulation of cardiomyocytes with TWEAK promoted nuclear translocation of NF-κB and subsequent induction of NF-κB dependent genes such as RANTES and MCP-1. Conversely, when cells were pretreated with siRNA against Fn14, NF-κB activation by TWEAK was inhibited. We here provide the first evidence of a stress-induced regulation of the TWEAK/Fn14 axis in cardiomyocytes implying a role of the TWEAK/Fn14 pathway in cardiac remodeling. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily that acts on responsive cells via binding to a cell surface receptor named fibroblast growth factor-inducible 14 (Fn14). TWEAK can regulate numerous cellular responses in vitro and in vivo. Recent studies have indicated that TWEAK and Fn14 are expressed in the central nervous system (CNS), and that in response to a variety of stimuli, including cerebral ischemia, there is an increase in TWEAK and Fn14 expression in perivascular astrocytes, microglia, endothelial cells, and neurons with subsequent increase in the permeability of the blood–brain barrier (BBB) and cell death. Furthermore, there is a growing body of evidence indicating that TWEAK induces the activation of the NF-κB in the CNS with release of proinflammatory cytokines and matrix metalloproteinases. In addition, inhibition of TWEAK activity by either treatment with a Fn14-Fc fusion protein or neutralizing anti-TWEAK antibodies has shown therapeutic efficacy in animal models of ischemic stroke, cerebral edema, and multiple sclerosis. [ABSTRACT FROM AUTHOR]

Inflammation participates in tissue repair through multiple mechanisms including directly regulating the cell fate of resident progenitor cells critical for successful regeneration. Upon surveying target cell types of the TNF ligand TWEAK, we observed that TWEAK binds to all progenitor cells of the mesenchymal lineage and induces NF-κB activation and the expression of pro-survival, pro-proliferative and homing receptor genes in the mesenchymal stem cells, suggesting that this pro-inflammatory cytokine may play an important role in controlling progenitor cell biology. We explored this potential using both the established C2C12 cell line and primary mouse muscle myoblasts, and demonstrated that TWEAK promoted their proliferation and inhibited their terminal differentiation. By generating mice deficient in the TWEAK receptor Fn14, we further showed that Fn14-deficient primary myoblasts displayed significantly reduced proliferative capacity and altered myotube formation. Following cardiotoxin injection, a known trigger for satellite cell-driven skeletal muscle regeneration, Fn14-deficient mice exhibited reduced inflammatory response and delayed muscle fiber regeneration compared with wild-type mice. These results indicate that the TWEAK/Fn14 pathway is a novel regulator of skeletal muscle precursor cells and illustrate an important mechanism by which inflammatory cytokines influence tissue regeneration and repair. Coupled with our recent demonstration that TWEAK potentiates liver progenitor cell proliferation, the expression of Fn14 on all mesenchymal lineage progenitor cells supports a broad involvement of this pathway in other tissue injury and disease settings. [ABSTRACT FROM AUTHOR]