TNF-like Weak Inducer Research Articles

Dithranol treatment of plaque-type psoriasis increases serum TNF-like weak inducer of apoptosis (TWEAK)

PurposeTNF-like weak inducer of apoptosis (TWEAK) mediates not only apoptosis, but also inflammation, cell growth and angiogenesis. The role of TWEAK in psoriasis remains unknown. The aim of the study was to assess serum levels of TWEAK in psoriatic patients before and after topical treatment with dithranol in relation to the clinical activity of the disease. Material and methodsSerum samples were collected from 40 patients with plaque type psoriasis before and after topical treatment with dithranol. The concentrations of serum TWEAK were measured by ELISA and next compared with 16 healthy controls. The data were analyzed with respect to Psoriasis Area and Severity Index (PASI). ResultsBaseline serum TWEAK concentrations of psoriatic patients (685±166pg/ml) were significantly greater compared to healthy controls (565±110pg/ml). Topical treatment resulted in further increase in serum TWEAK (749±179pg/ml; p<0.01). In case of patients with initial serum TWEAK concentrations above the median, PASI after topical treatment was lower compared to the individuals with initial TWEAK below the median. ConclusionAccording to the study, serum Tweak was increased in psoriasis patients compared with controls. Moreover, dithranol topical treatment caused further increase in serum TWEAK. Also, a higher effectiveness of topical treatment was observed in case of patients with higher initial TWEAK concentrations. The results suggest a potential role of TWEAK in psoriasis therapy.

Soluble TWEAK and Major Adverse Cardiovascular Events in Patients with CKD.

Soluble TNF-like weak inducer of apoptosis (sTWEAK) is a proinflammatory cytokine belonging to the TNF superfamily. sTWEAK concentrations have been associated with the presence of CKD and cardiovascular disease (CVD). We hypothesized that sTWEAK levels may relate to a higher prevalence of atherosclerotic plaques, vascular calcification, and cardiovascular outcomes observed in patients with CKD. A 4-year prospective, multicenter, longitudinal study was conducted in 1058 patients with CKD stages 3-5D (mean age =58±13 years old; 665 men) but without any history of CVD from the NEFRONA Study (a study design on the prevalence of surrogate markers of CVD). Ankle-brachial index and B-mode ultrasound were performed to detect the presence of carotid and/or femoral atherosclerotic plaques together with biochemical measurements and sTWEAK assessment. Patients were followed for cardiovascular outcomes (follow-up of 3.13±1.15 years). Patients with more advanced CKD had lower sTWEAK levels. sTWEAK concentrations were independently and negatively associated with carotid intima-media thickness. sTWEAK levels were lower in patients with carotid atherosclerotic plaques but not in those with femoral plaques. After adjustment by confounders, the odds ratio (OR) for presenting carotid atherosclerotic plaques in patients in the lowest versus highest tertile of sTWEAK was 4.18 (95% confidence interval [95% CI], 2.89 to 6.08; P<0.001). Furthermore, sTWEAK levels were lower in patients with calcified carotid atherosclerotic plaques. The OR for presenting calcified carotid plaques was 1.77 (95% CI, 1.06 to 2.93; P=0.02) after multivariable adjustment. After the follow-up, 41 fatal and 68 nonfatal cardiovascular events occurred. In a Cox model, after controlling for potential confounding factors, patients in the lowest tertile of sTWEAK concentrations had a higher risk of fatal and nonfatal cardiovascular events (hazard ratio [HR], 2.40; 95% CI, 1.33 to 4.33; P=0.004) and cardiovascular mortality (HR, 2.67; 95% CI, 1.05 to 6.76; P=0.04). Low sTWEAK levels were associated with the presence of carotid atherosclerotic plaques in patients with CKD. Additionally, lower sTWEAK levels were associated with a higher risk of cardiovascular morbidity and mortality.

Intracerebroventricular administration of TNF-like weak inducer of apoptosis induces depression-like behavior and cognitive dysfunction in non-autoimmune mice

Fn14, the sole known signaling receptor for the TNF family member TWEAK, is inducibly expressed in the central nervous system (CNS) in endothelial cells, astrocytes, microglia, and neurons. There is increasing recognition of the importance of the TWEAK/Fn14 pathway in autoimmune neurologic conditions, including experimental autoimmune encephalomyelitis and neuropsychiatric lupus. Previously, we had found that Fn14 knockout lupus-prone MRL/lpr mice display significantly attenuated neuropsychiatric manifestations. To investigate whether this improvement in disease is secondary to inhibition of TWEAK/Fn14 signaling within the CNS or the periphery, and determine whether TWEAK-mediated neuropsychiatric effects are strain dependent, we performed intracerebroventricular (ICV) injection of Fc-TWEAK or an isotype matched control protein to C57Bl6/J non-autoimmune mice. We found that Fc-TWEAK injected C57Bl6/J mice developed significant depression-like behavior and cognitive dysfunction. Inflammatory mediators associated with lupus brain disease, including CCL2, C3, and iNOS, were significantly elevated in the brains of Fc-TWEAK treated mice. Furthermore, Fc-TWEAK directly increased blood brain barrier (BBB) permeability, as demonstrated by increased IgG deposition in the brain and reduced aquaporin-4 expression. Finally, Fc-TWEAK increased apoptotic cell death in the cortex and hippocampus. In conclusion, TWEAK can contribute to lupus-associated neurobehavioral deficits including depression and cognitive dysfunction by acting within the CNS to enhance production of inflammatory mediators, promote disruption of the BBB, and induce apoptosis in resident brain cells. Our study provides further support that the TWEAK/Fn14 signaling pathway may be a potential therapeutic target for inflammatory diseases involving the CNS.

Role of the TWEAK/Fn14 pathway in autoimmune diseases.

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.

Reduced soluble TNF-like weak inducer of apoptosis (sTWEAK) and increased frap in postmenopausal women with metabolic syndrome

Background Recent evidence in the literature has reported the association between the soluble bioactive form of TNF-like weak inducer of apoptosis (sTWEAK) to insulin resistance, type 2 DM, chronic kidney disease, and atherosclerosis. To date, just a single study has evaluated this novel inflammatory cytokine in Metabolic Syndrome (MetS), showing a reduction in the circulating levels of sTWEAK in elder Caucasian patients (>97% hypertensive) at high cardiovascular risk. Nevertheless, is not known whether individuals from a mixed population at the primary care may exhibit or not similar changes.

MCP-1 and soluble TWEAK levels are independently associated with coronary artery disease severity in patients with chronic kidney disease

Purpose: Patients diagnosed with chronic kidney disease (CKD) have a greater rate of cardiovascular mortality when compared with the general population. The soluble form of TNF-like weak inducer of apoptosis (TWEAK) and monocyte chemoattractan protein 1 (MCP-1) play important roles in cellular proliferation, migration and apoptosis. The current study aimed to analyze whether soluble TWEAK (sTWEAK) and MCP-1 levels are associated with the severity of coronary arterial disease (CAD) in CKD patients. Methods: Ninety-seven patients diagnosed with CKD stages 2–3 according to their estimated glomerular filtration rate and the presence of kidney injury were included in the study. Plasma sTWEAK and MCP-1 concentrations were determined using commercially available ELISA kits. Coronary angiographies were performed through femoral artery access using the Judkins technique. Results: Correlation analysis of sTWEAK and Gensini scores showed significant association (p < 0.01, r2 = 0.287). Also significant correlation has been found in MCP-1 levels and Gensini scores (p < 0.01, r2 = 0.414). When patients were divided into two groups with a limit of 17 according to their Gensini score, sTWEAK levels indicated a statistically significant difference (p < 0.01). Conclusions: Our findings support a relationship between sTWEAK and MCP-1 levels and CAD in CKD stages 2–3 patients.

The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics.

Fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is normally expressed at low levels in healthy tissues but expression is significantly increased after tissue injury and in many solid tumor types, including glioblastoma (GB; formerly referred to as 'GB multiforme'). GB is the most common and aggressive primary malignant brain tumor and the current standard-of-care therapeutic regimen has a relatively small impact on patient survival, primarily because glioma cells have an inherent propensity to invade into normal brain parenchyma, which invariably leads to tumor recurrence and patient death. Despite major, concerted efforts to find new treatments, a new GB therapeutic that improves survival has not been introduced since 2005. In this review article, we summarize studies indicating that (i) Fn14 gene expression is low in normal brain tissue but is upregulated in advanced brain cancers and, in particular, in GB tumors exhibiting the mesenchymal molecular subtype; (ii) Fn14 expression can be detected in glioma cells residing in both the tumor core and invasive rim regions, with the maximal levels found in the invading glioma cells located within normal brain tissue; and (iii) Fn14 engagement as well as Fn14 overexpression can stimulate glioma cell migration, invasion and resistance to chemotherapeutic agents in vitro. We also discuss two new therapeutic platforms that are currently in development that leverage Fn14 overexpression in GB tumors as a way to deliver cytotoxic agents to the glioma cells remaining after surgical resection while sparing normal healthy brain cells.

TWEAK/Fn14 Signaling Involvement in the Pathogenesis of Cutaneous Disease in the MRL/lpr Model of Spontaneous Lupus

TNF-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14, and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB signaling. Ultraviolet-B irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo, and increased RANTES production. MRL/lpr Fn14 knockout lupus mice were compared with MRL/lpr Fn14 wild-type mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 knockout mice had markedly attenuated cutaneous disease as compared to their Fn14 wild-type littermates, as evidenced by the well maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus, and suggest a possible target for therapeutic intervention.

TWEAK/Fn14 interaction promotes oxidative stress through NADPH oxidase activation in macrophages.

The interaction between TNF-like weak inducer of apoptosis (TWEAK, Tnfsf12) and the receptor, fibroblast growth factor-inducible 14 (Fn14), regulates vascular damage through different mechanisms, including inflammation. Oxidative stress plays a major role in inflammation and the development of atherosclerosis, but the relationship between TWEAK and oxidative stress is, however, poorly understood. In this study, we found that TWEAK and Fn14 are co-localized with the NADPH subunits, p22phox and Nox2, in human advanced atherosclerotic plaques. Using primary human macrophages and a murine macrophage cell line, we demonstrate that TWEAK promotes ROS production and enhances NADPH oxidase activity. Hence, we show a direct involvement of the TWEAK-Fn14 axis in oxidative stress, as genetic silencing of Fn14 or Nox2 abrogates the TWEAK-induced ROS production. Furthermore, our results point at Rac1 as an upstream mediator of TWEAK during oxidative stress. Finally, using an in vivo murine model we confirmed the major role of TWEAK in oxidative stress, as genetic silencing of Tnfsf12 in an ApoE(-/-) background reduces the number of DHE and 8-hydroxydeoxyguanosine-positive macrophages by 50%. Our results suggest that TWEAK regulates vascular damage by stimulating ROS production in an Nox2-dependent manner. These new insights into the TWEAK/Fn14 axis underline their potential use as therapeutic targets in atherosclerosis.

Fn14 deficiency protects lupus-prone mice from cutaneous lesions induced by UVB irradiation (BA6P.135)

Abstract Cutaneous lupus erythematosus (CLE) in one of its various forms is seen in the majority of patients with systemic lupus. Photosensitivity is common in lupus, and sunlight (via UVB irradiation) is a well-recognized trigger of CLE. A TNF superfamily member, TNF-like weak inducer of apoptosis (TWEAK), is a soluble cytokine that binds to its sole known signaling receptor, Fn14. TWEAK and Fn14 are upregulated with inflammation and/or injury, and this pathway is important in critical biologic processes including angiogenesis, cell survival, and local inflammation. Previously, we found that lupus-prone MRL/lpr mice deficient for Fn14 (Fn14 KO) had markedly attenuated skin disease (which develops spontaneously in this strain) as compared to Fn14 wild-type (WT) mice. Here, we demonstrate that absence of the Fn14 receptor is protective against the expected UVB-induced eruption. MRL/lpr Fn14 WT mice developed significantly more severe skin involvement following exposure to UVB when compared to strain, age, and gender matched Fn14 KO mice. Histologically, MRL/lpr Fn14 WT mice had significantly more apoptotic keratinocytes, basement membrane degeneration, and dermal inflammation comprised of macrophages following UVB. RT-PCR revealed higher levels of CXCL9, CXCL10, CXCL11 and RANTES in MRL/lpr Fn14 WT mice. Our data suggests a novel role for the TWEAK/Fn14 signaling pathway in the induction of cutaneous lupus lesions following UVB.

TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice

Neuropsychiatric disease is one of the most common manifestations of human systemic lupus erythematosus, but the mechanisms remain poorly understood. In human brain microvascular endothelial cells in vitro, TNF-like weak inducer of apoptosis (TWEAK) decreases tight junction ZO-1 expression and increases the permeability of monolayer cell cultures. Furthermore, knockout (KO) of the TWEAK receptor, Fn14, in the MRL/lpr lupus mouse strain markedly attenuates neuropsychiatric disease, as demonstrated by significant reductions in depressive-like behavior and improved cognitive function. The purpose of the present study was to determine the mechanisms by which TWEAK signaling is instrumental in the pathogenesis of neuropsychiatric lupus (NPSLE). Evaluating brain sections of MRL/lpr Fn14WT and Fn14KO mice, we found that Fn14KO mice displayed significantly decreased cellular infiltrates in the choroid plexus. To evaluate the integrity of the blood brain barrier (BBB) in MRL/lpr mice, Western blot for fibronectin, qPCR for iNOS, and immunohistochemical staining for VCAM-1/ICAM-1 were performed. We found preserved BBB permeability in MRL/lpr Fn14KO mice, attributable to reduced brain expression of VCAM-1/ICAM-1 and iNOS. Additionally, administration of Fc-TWEAK intravenously directly increased the leakage of a tracer (dextran-FITC) into brain tissue. Furthermore, MRL/lpr Fn14KO mice displayed reduced antibody (IgG) and complement (C3, C6, and C4a) deposition in the brain. Finally, we found that MRL/lpr Fn14KO mice manifested reduced neuron degeneration and hippocampal gliosis. Our studies indicate that TWEAK/Fn14 interactions play an important role in the pathogenesis of NPSLE by increasing the accumulation of inflammatory cells in the choroid plexus, disrupting BBB integrity, and increasing neuronal damage, suggesting a novel target for therapy in this disease.

TWEAK enhances TGF-β-induced epithelial-mesenchymal transition in human bronchial epithelial cells.

BackgroundChronic airway inflammatory disorders, such as asthma, are characterized by airway inflammation and remodeling. Chronic inflammation and damage to the airway epithelium cause airway remodeling, which is associated with improper epithelial repair, and is characterized by elevated expression of transforming growth factor-β (TGF-β). Epithelial-mesenchymal transition (EMT) is an important mechanism during embryonic development and tissue remodeling whereby epithelial cells gain the capacity to increase motility by down-regulation of epithelial markers and up-regulation of mesenchymal markers. TGF-β is a central inducer of EMT, and TGF-β-induced EMT is enhanced by pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β. We investigated whether the pro-inflammatory cytokine TWEAK (TNF-like weak inducer of apoptosis) enhanced TGF-β1-induced EMT in the human bronchial epithelial cell line BEAS-2B.MethodsQuantitative RT-PCR and western blotting were used to define alterations in epithelial and mesenchymal marker expression in BEAS-2B cells. The cells were assessed for 48 h after stimulation with TGF-β1 alone or in combination with TWEAK.ResultsTGF-β1 induced spindle-like morphology and loss of cell contact, and reduced the expression of epithelial marker E-cadherin and increased the expression of mesenchymal markers N-cadherin and vimentin. Our data, for the first time, show that TWEAK reduced the expression of E-cadherin, and that co-treatment with TGF-β1 and TWEAK enhanced the TGF-β1-induced features of EMT. Moreover, hyaluronan synthase 2 expression was up-regulated by a combination with TGF-β1 and TWEAK, but not TNF-α. We also demonstrated that the Smad, p38 MAPK, and NF-κB signaling pathways, and the transcriptional repressor ZEB2 might mediate N-cadherin up-regulation by TGF-β1 in combination with TWEAK.ConclusionsThese findings suggest that the pro-inflammatory cytokine TWEAK and TGF-β1 have synergistic effects in EMT and may contribute to chronic airway changes and remodeling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0207-5) contains supplementary material, which is available to authorized users.

TWEAK/Fn14 system and crescent formation in IgA nephropathy

BackgroundThe TNF-like weak inducer of apoptosis (TWEAK) contributes to kidney inflammation producing secretion by renal cells. The present study examined whether the level of TWEAK is associated with histologic findings in patients with IgA nephropathy (IgAN).MethodsThe levels of urinary TWEAK (uTWEAK) from 116 IgAN patients, 50 non-IgA kidney disease patients, and 50 healthy individuals were measured by ELISA. Histological findings of renal biopsy specimens of patients with IgAN were evaluated according to the Oxford classification and histological classification for IgAN in Japan. We investigated the expression of TWEAK/Fn14 in renal tissues of those patients and assessed the effect of TWEAK in glomerular mesangial cells and podocytes.ResultsThe levels of uTWEAK in the patients with IgAN and other renal diseases were significantly higher than in the healthy controls (P < 0.001). In the IgAN patients, the levels of uTWEAK correlated significantly with urinary protein excretion and extracapillary proliferation (r = 0.54, P < 0.001 and r = 0.32, P < 0.001, respectively). In a comparison of the levels of uTWEAK at diagnosis with that of follow-up, the levels of uTWEAK in patients with clinical and partial remission decreased significantly. We showed not only increased expression of both TWEAK and Fn14 in IgAN patients with glomerular crescents but also TWEAK-induced cell motility in podocytes.ConclusionsThe relationship between the levels of uTWEAK and clinicopathological findings observed in this study suggests that TWEAK/Fn14 system affects crescent formation and proteinuria in patients with IgAN.

Muscle inflammation susceptibility: a prognostic index of recovery potential after hip arthroplasty?

While elective total hip arthroplasty (THA) for end-stage osteoarthritis (OA) improves pain, mobility function, and quality of life in most cases, a large proportion of patients suffer persistent muscle atrophy, pain, and mobility impairment. Extensive skeletal muscle damage is unavoidable in these surgical procedures, and it stands to reason that poor recovery and long-term mobility impairment among some individuals after THA is linked to failed muscle regeneration and regrowth following surgery and that local muscle inflammation susceptibility (MuIS) is a major contributing factor. Here we present results of two integrated studies. In study 1, we compared muscle inflammation and protein metabolism signaling in elective THA (n=15) vs. hip fracture/trauma (HFX; n=11) vs. nonsurgical controls (CON; n=19). In study 2, we compared two subgroups of THA patients dichotomized into MuIS⁺ (n=7) or MuIS⁻ (n=7) based on muscle expression of TNF-like weak inducer of apoptosis (TWEAK) receptor (Fn14). As expected, HFX demonstrated overt systemic and local muscle inflammation and hypermetabolism. By contrast, no systemic inflammation was detected in elective THA patients; however, local muscle inflammation in the perioperative limb was profound in MuIS⁺ and was accompanied by suppressed muscle protein synthesis compared with MuIS⁻. Muscle from the contralateral limb of MuIS⁺ was unaffected, providing evidence of a true inflammation susceptibility localized to the muscle surrounding the hip with end-stage OA. We suggest MuIS status assessed at the time of surgery may be a useful prognostic index for muscle recovery potential and could therefore provide the basis for a personalized approach to postsurgery rehabilitation.

Mechanisms of keratinocyte death in Stevens-Johnsonsyndrome/toxic epidermal necrolysis

The apoptosis of keratinocytes involves drug metabolism and immune mechanism. The former mainly refers to the induction of apoptosis by active electrophilic drug metabolites through the mitochondrial pathway. Comparatively, the immune mechanism is more complex with the involvement of many immune cells including CD8+ cytotoxic T cells, natural killer cells, monocytes and regulatory T cells. Some cytokines, such as tumor necrosis factor α(TNF-α), soluble FasL, granulysin, TNF-related apoptosis-inducing ligand(TRAIL)and TNF-like weak inducer of apoptosis(TWEAK), contribute to the amplification of apoptosis. The necrosis of keratinocytes is considered to be associated with the alarm family members S100A, α-defensins and high mobility group protein B1. Key words: Stevens-Johnson syndrome; Epidermal necrolysis, toxic; Keratinocytes; Apoptosis

Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement.

Patients with hypogonadism have poor cardiovascular and metabolic outcomes, and the effect of testosterone replacement therapy (TRT) is not clear. We investigated the presence of inflammation, insulin resistance and endothelial dysfunction in an unconfounded population of congenital hypogonadotrophic hypogonadism (CHH) and the effect of TRT on these subjects. A total of 60 patients with CHH (mean age 21.82±2.22 years) and 70 healthy control subjects (mean age 21.32±1.13 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), TNF-like weak inducer of apoptosis (TWEAK), high sensitive C reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured before and after TRT. The patients had higher Waist Circumferences (WC) (p=0.009), Diastolic Blood Pressures (p=0.02), Triglycerides (p=0.03), ADMA, insulin and HOMA-IR levels (p<0.001 for all) and lower TWEAK levels (p<0.001), compared to the healthy controls. After 5.56 ± 2.04 months of TRT, the patients had significantly elevated systolic blood pressures (p=0.01), body mass indexes and WC (p<0.001 and p=0.001 respectively) and decreased total and HDL cholesterol levels (p=0.032 and p<0.001 respectively). ADMA levels significantly increased (p=0.003), while the alterations in TWEAK, hsCRP and HOMA-IR were not significant. The results of the present study show that endothelial dysfunction, inflammation and insulin resistance are prevalent even in the very young subjects with CHH, who have no metabolic or cardiac problems at present. This increased cardiometabolic risk however, do not improve but even get worse after six months of TRT. Long term follow-up studies are warranted to investigate the unfavorable cardiometabolic effects of TRT.

Role of Fn14 in acute alcoholic steatohepatitis in mice.

TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14(+) progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl₄ for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl₄ treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline content, and quantitative immunohistochemistry. During liver injury, Fn14 expression, apoptosis, inflammation, hepatocyte replication, progenitor and myofibroblast accumulation, and fibrosis increased in WT mice fed either diet. Mice fed either diet expressed similar TWEAK/Fn14 levels, but ETOH-fed mice had higher TNF-α expression. The ETOH-fed group developed more apoptosis, inflammation, fibrosis, and regenerative responses. Fn14 deletion did not reduce hepatic TNF-α expression but improved all injury parameters in mice fed the control diet. In ETOH-fed mice, Fn14 deletion inhibited TNF-α induction and increased acute mortality, despite improvement in liver injury. Fn14 mediates wound-healing responses that are necessary to survive acute liver injury during alcohol exposure.

Elevated levels of TWEAK in skeletal muscle promote visceral obesity, insulin resistance, and metabolic dysfunction.

Skeletal muscle is responsible for the majority of glucose disposal in body. Impairment in skeletal muscle glucose handling capacity leads to the state of insulin resistance. The TNF-like weak inducer of apoptosis (TWEAK) cytokine has now emerged as a major regulator of skeletal muscle mass and function. However, the role of TWEAK in skeletal muscle metabolic function remains less understood. Here, we demonstrate that with progressive age, skeletal muscle-specific TWEAK-transgenic (TWEAK-Tg) mice gain increased body weight (∼16%) and fat mass (∼64%) and show glucose intolerance and insulin insensitivity. TWEAK-Tg mice also exhibit adipocyte hypertrophy in the epididymal fat. Oxygen uptake, voluntary physical activity, and exercise capacity were significantly reduced in TWEAK-Tg mice compared with controls. Overexpression of TWEAK inhibited (∼31%) 5' AMP-activated protein kinase (AMPK) and reduced (∼31%) the levels of glucose transporter type 4 (GLUT4) without affecting the Akt pathway. TWEAK also inhibited insulin-stimulated glucose uptake (∼32%) and repressed the levels of GLUT4 (∼50%) in cultured myotubes from C57BL6 mice. TWEAK represses the levels of Krüppel-like factor 15; myocyte enhancer factor 2, and peroxisome proliferator-activated receptor-γ coactivator-1α, which are required for the activation of the GLUT4 locus. Collectively our study demonstrates that elevated levels of TWEAK in skeletal muscle cause metabolic abnormalities. Inhibition of TWEAK could be a potential approach to prevent weight gain and type 2 diabetes.

The Relationship between Plasma Soluble Tnf-like Weak Inducer of Apoptosis Level and Inflammatory Markers in Patients with Type 2 Diabetes Mellitus

Soluble TNF-like weak inducer of apoptosis (sTWEAK) is a member of the TNF super family with many biological activities. There is a limited number of studies on the role of sTWEAK in chronic kidney disease. We aimed in this study to examine the relation of sTWEAK with albuminuria and inflammatory markers in patients with type 2 diabetes mellitus (DM). One hundred and eighteen diabetic patients with varying levels of albuminuria were included. Group 1 comprised patients with albuminuria less than 30 mg/day, while Group 2 and Group 3 were composed of patients with albuminuria between 30–300 mg/day or more than 300 mg/day, respectively. Groups were compared for sTWEAK levels besides demographic, clinical and biochemical data. There was no difference between groups regarding sTWEAK and TNF-α levels. IL-1 levels in Group 1 were higher than in Group 3. hsCRP levels were significantly higher in Group 3 compared to other groups. Use of a renin angiotensin system blocker did not have any effect on sTWEAK, TNF-α and hsCRP levels, while IL-1 level was significantly lower in patients using a renin angiotensin blocker. A statistically significant positive correlation was detected between sTWEAK and IL-1 levels (r=0.245; p=0.008). The groups were found to be similar regarding sTWEAK and TNF-α level. This finding may be interpreted as there being no effect of proteinuria on sTWEAK levels. But the close correlation between proteinuria and IL-1, and between IL-1 and sTWEAK may be a clue for an indirect relationship. Lack of difference between groups regarding sTWEAK levels may be due to involvement of patients with GFR more than 60 ml/minute only.

The Prognostic Role of Inflammation and Hormones in Patients with Metastatic Cancer with Cachexia

ABSTRACT Aim: We aimed to investigate the possiple etiologic factors of cachexia. Methods: Forty-six patients diagnosed with cancer cachexia and 34 healthy controls were included in the study. Serum total testosterone, interleukin 1 (IL) alpha and beta, IL 6, tumor necrosis factor (TNF) alpha, orexin, galanin, neuropeptide Y, TNF-like weak inducer of apoptosis (TWEAK) and TNF receptor-associated factor 6 (TRAF 6) and C reactive protein (CRP) levels were investigated. Results: There were 36 male and 10 female patients in the cachexia group, and 24 male and 10 female patients in the control group. There was no statistcally significant difference for age, white blood cell count, and liver functions between the groups.The most common type of cancer in the cachexia group was gstro-esophageal cancers (n = 24); the remaining 7 patients had pacreatic cancer,7 had lung cancer and, 4 had colorectal cancer, 2 had ovarian cancer, 1 had breast cancer and 1 had laryngeal caner. All 46 patients had systemic metastasis at the time of the study and all of the patients died during the study follow up. Median overall survival (OS) of the cachexia group after the diagnosis of cachexia was 8 (1-25) months. There were statistically significant relationships between OS and BMI, serum CRO, TRAF6, albumin and LDH levels in the cachexia group (P= 0.009, 0.0001, 0.017, 0.001 and 0.001, respectively). In addition to cachexia group, serum CRP, testosterone, and TNF alpha levels were statistically significantly correlated with OS in refractory cachexia (P = 0.0001, 0.001 and 0.017, respectively). Conclusions: Although cachexia presents with a multifactorial etiopathogenesis, few of the factors affect the OS. Our novel results were serum CRP, albumin, LDH and TRAF 6 levels have a higher association with OS in patients with cancer cachexia compared with the many other parameters. An ongoing cachexia also called refractory cachexia is a recent definition. This end- stage term of cancer duration may be predicted by decreasing serum testosterone and increasing serum TNF alpha levels,as well as serum CRP levels. Disclosure: All authors have declared no conflicts of interest.