Weak Inducer Research Articles

Fibroblast growth factor inducible 14 signaling facilitates anti-dsDNA IgG penetration into mesangial cells.

Anti-double-stranded DNA (dsDNA) antibodies induce renal damage in patients with systemic lupus erythematosus by triggering fibrotic processes in kidney cells. However, the precise mechanism underlying penetration of anti-dsDNA immunoglubolin G (IgG) into cells remains unclear. This study was designed to investigate the effect of tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor inducible 14 (Fn14) signaling on anti-dsDNA IgG penetration into cells. Mesangial cells were cultured in vitro, and stimulated with TWEAK and anti-dsDNA IgG. The results revealed that TWEAK dose-dependently enhanced cellular internalization of anti-dsDNA IgG and the expression of high-mobility group box 1 (HMGB1). In addition, TWEAK and anti-dsDNA IgG synthetically downregulate suppressor of cytokine signaling 1,and induce the expression of various fibrotic factors. Furthermore, inhibition of HMGB1 attenuates the enhancement effect of TWEAK on anti-dsDNA IgG internalization. The TWEAK upregulation of HMGB1 involves the nuclear factor-κB and phosphatidylinositide 3-kinase/protein kinase B pathways. Therefore, TWEAK/Fn14 signaling contributes to the penetration of anti-dsDNA IgG and relevant fibrotic processes in mesangial cells.

4221 Lower Serum TWEAK Concentration is a Biomarker for Mortality in Community Acquired Pneumonia

OBJECTIVES/GOALS: To determine the relationship among serum concentration of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and mortality in community-acquired pneumonia (CAP) patients. METHODS/STUDY POPULATION: This is a multicenter 2-year cohort study in Spain, designed to better understand the role of sTWEAK concentrations in CAP patients. CAP patients were prospectively enrolled in two University hospitals and sTWEAK was measured within the first 24 hours of ICU admission. Samples were collected and stored for laboratory analyses. To detect sTWEAK in human samples, we used a commercially available ELISA kit following manufacturer’s instructions. Demographic patients’ characteristics and ICU mortality were prospectively collected. Descriptive statistics and logistical regressions were used to assess the proposed aims. RESULTS/ANTICIPATED RESULTS: A total of forty-three patients were included in the study (10 healthy users, 10 uninfected controls and 23 CAP patients). In comparison to healthy volunteers, patients admitted to the hospital (both, infected and non-infected) had lower level of sTWEAK. During hospital admission, 7 (17%) patients died. Patients whom died during ICU stay due to CAP, had significantly lower levels of sTWEAK when comparing with patients whom survived (Median [IQR]; 509.35 [357.49, 953.92] Vs 1103.03 [716.93, 1663.16]; p = 0.015). In contrast, patients that developed shock did not have different concentrations of sTWEAK (Median [IQR]; 1008.04 [531.87, 1390.80] Vs 1062.29 [575.24, 1598.83], p = 0.84). DISCUSSION/SIGNIFICANCE OF IMPACT: Community-acquired pneumonia (CAP) is the first cause of death in underdeveloped countries. CAP is a pulmonary infection that creates a proinflammatory environment not just locally but also systemically, secondary to upregulation of molecular cascades with a wide variety of proteins being released perpetuating this inflammation and tissue damage. Several of these molecules have been described and linked to a greater risk of inhospital complications, longer length of hospital stay and mortality. TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF-alpha superfamily, involved in immune response, cell growth, angiogenesis, NF-kB activation and apoptosis induction in tumor cells. It is known that serum-TWEAK plays a role in inflammatory processes, however, its behavior is unknown in patients with CAP. Therefore, this study aims to identify whether there is a relationship between serum concentration of TWEAK and prognosis in CAP patients. To our knowledge, this is the first study to shown that concentration of sTWEAK within the first 24 hours of ICU admission is lower in patients with CAP. Moreover, patients whom died during ICU admission due to CAP, have lower sTWEAK levels. This biomarker may identify patients at higher risk of dying due to CAP and may represent severe CAP. However, further studies are needed to confirm these findings.

Prediagnostic serum polychlorinated biphenyl concentrations and primary liver cancer: A case-control study nested within two prospective cohorts

BackgroundPolychlorinated biphenyls (PCBs) were used in electrical equipment and a range of construction materials. Although banned in the United States and most of Europe in the 1970s, they are highly persistent in the environment and bioaccumulate. Whether PCBs are associated with liver cancer risk at general population levels is unknown. MethodsThis study consisted of 136 incident liver cancer cases and 408 matched controls from the Kaiser Permanente Northern California Multiphasic Health Checkup (MHC) cohort and 84 cases and 252 matched controls from the Norwegian Janus cohort. Sera collected in the 1960s–1980s were measured for 37 PCB congeners and markers of hepatitis B (HBV) and C (HCV) infection. Odds ratios (OR) and 95% confidence intervals (CI) for tertiles of each lipid-adjusted PCB were estimated from conditional logistic regression. We also examined the molar sum of congeners in groups: total PCBs; low, medium, and high chlorination; and Wolff functional groups. ResultsConcentrations of individual congeners from the 1960s/1970s sera ranged from 1.3-123.0 and 1.4–116.0 ng/g lipid among MHC cases and controls, respectively, and from 1.9-258.0 and 1.9–271.0 ng/g lipid among Janus cases and controls, respectively. Among MHC participants with sera from the 1960s, collected an average of 27 years before diagnosis among cases, the top tertile of PCBs 151, 170, 172, 177, 178, 180, and 195 was significantly associated with elevated odds of liver cancer (OR range = 2.01–2.38); most of these congeners demonstrated exposure-response trends. For example, ORtertile 3vs1 = 2.38 (95% CI: 1.22–4.64, p-trend = 0.01) for PCB 180. As a group, Wolff group 1b congeners, which are biologically persistent and weak phenobarbital inducers, were associated with increased odds. In MHC participants, ever vs. never HBV or HCV infection modified the PCB-liver cancer associations. There was little evidence of an association between PCBs and odds of liver cancer among the Janus cohort. DiscussionWe observed associations between a number of PCB congeners and increased odds of liver cancer among MHC, but not Janus, participants with sera from the 1960s/1970s.

Low TWEAK expression indicates poor survival and is correlated with sparse TIICs in lung adenocarcinoma (LUAD).

e21017 Background: Lung adenocarcinoma (LUAD) occupies the most of non-small cell lung cancer (NSCLC) and shows promising response to PD-1 immunotherapy, but immune escape will cause treatment failure indicating poor prognosis. TWEAK (Tumor necrosis factor-related weak inducer of apoptosis, also known as TNFSF12) combining with its receptor FN14 (fibroblast growth factor–inducible 14) mediates crucial innate and adaptive immune pathways to promote the progression of multiple autoimmune diseases. So we assumed that TWEAK is a prognostic predictor and related with tumor-infiltrating immune cells (TIICs) in LUAD. Methods: TWEAK expression of LUAD was primarily investigated in The Cancer Immunome Atlas (TCIA) and then validated in Tumor Immune Estimation Resource (TIMER) databases. We assessed the effect of TWEAK on the survival via the Kaplan-Meier plotter, GEPIA2 (gene expression profiling interactive analysis) and PrognoScan databases. The relation between TWEAK and TIICs was explored in TIMER and TCIA, as well as the correlation of TWEAK and FN14 was analyzed in TIMER and GEPIA2. Results: Low TWEAK expression was significantly associated with poor relapse-free survival (RFS) (HR = 0.62, 95% CI = 0.4~0.97, logrank P = 0.035) and overall survival (OS) (HR = 0.61, 95% CI = 0.46~0.83, logrank P = 0.0012) in LUAD from Kaplan-Meier plotter. Similar impacts of TWEAK on the survival were validated in GEPIA2 and four independent cohorts from PrognoScan (jacob-00182-CANDF, GSE13213, jacob-00182-MSK and GSE31210). Moreover, reduced TWEAK expression was closely related with the paucity of TIICs which contributed to poor OS, including central memory CD8 T cells, plasmacytoid dendritic cells, activated CD8 T cells, monocytes, T follicular helper cells, immature B cells and eosinophils. In addition, TWEAK expression was positively related with the expression level of FN14 in both GEPIA2(R = 0.13, P= 0.0031) and TIMER (partial.cor = 0.212, P= 2.04e-06). Conclusions: Low TWEAK expression maybe indicate poor prognosis in LUAD, and correlated with the impaired infiltration of immune cells in the tumor region. The defective TWEAK/FN14 pathway possibly accounts for these observations, but the underlying mechanism needs to be further explored.

Tumor necrosis factor like weak inducer of apoptosis (TWEAK) Promotes Inflammatory Activity in Keratinocytes with IL-17 and TNF to Drive Psoriasis

Abstract Psoriasis is an autoimmune skin disease caused by hyper-proliferation of keratinocytes driven by distinct inflammatory cells making cytokines such as IL-17 and TNF. Our previous studies with knockout animals revealed that the TNF-related cytokine TWEAK (TNFSF12) was also a critical contributor to skin inflammation and could be a potential therapeutic target in psoriasis. As Fn14, the receptor for TWEAK, is expressed by keratinocytes, we examined the inflammatory effects of TWEAK alone and with IL-17A and TNF in modulating psoriatic genes in human keratinocytes using RNA-seq. We found that TWEAK upregulated the expression of multiple chemokines and cytokines, such as IL-36G, IL-23A, IL-19, CCL5, CCL20, and other inflammation-associated genes, that have previously been found highly expressed in the skin of patients with psoriasis. TWEAK’s action was partially overlapping with IL-17 and TNF, but interestingly, in combination with IL-17 or TNF, TWEAK had strong synergistic effects in enhancing the expression of a number of these inflammatory genes. We then tested the impact of TWEAK neutralization on already existing skin inflammation in an imiquimod-induced psoriasis model. Mice treated therapeutically with anti-TWEAK showed significantly decreased numbers of immune cell infiltrates in the skin, with fewer γδ T cells, neutrophils and macrophages. These mice also exhibited a marked reduction in epidermal thickening, similar to mice treated with anti-IL-17 alone. Furthermore, co-neutralization of TWEAK and IL-17 demonstrated a greater effect in terms of reducing clinical symptoms. These data suggest that blocking TWEAK could be considered as a potential therapeutic avenue in humans to overcome the pathophysiology of psoriasis.

Is serum TWEAK a useful biomarker of neuropsychiatric systemic lupus erythematosus?

The aim of this study was to determine the role of the tumor necrosis factor like weak inducer of apoptosis (TWEAK) as a serum biomarker of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE). Levels of TWEAK levels were measured in sera of 92 patients with systemic lupus erythematosus (SLE), including 28 patients with neuropsychiatric lupus, and in 59 healthy controls using ELISA. All SLE patients underwent rheumatological, neurological and psychiatric assessment. We found no significant differences in TWEAK levels, between SLE patients and the healthy controls (p=0.2411). Similarly, no difference was observed between subgroup of NPSLE and healthy controls (p=0.7658). The mean SLE disease activity (SLEDAI) was 13.25. No correlations between TWEAK levels with disease activity (SLEDAI, r=0.2113, p=0.2805) or the most common NPSLE manifestations such as headache (r=0.2079), seizures (r=0.1101), cerebrovascular disease (r= 0.2347), cognitive dysfunction (r=0.1597) and anxiety (r=0.1397) were observed. Our data do not support the use of serum TWEAK as a discriminating biomarker for NPSLE. The role of the TWEAK in NPSLE remains to be investigated.

Sequential Interferon β-Cisplatin Treatment Enhances the Surface Exposure of Calreticulin in Cancer Cells via an Interferon Regulatory Factor 1-Dependent Manner.

Immunogenic cell death (ICD) refers to a unique form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Accumulating evidence indicates that the efficacy of conventional anticancer agents relies on not only their direct cytostatic/cytotoxic effects but also the activation of antitumor ICD. Common anticancer ICD inducers include certain chemotherapeutic agents (such as anthracyclines, oxaliplatin, and bortezomib), radiotherapy, photodynamic therapy (PDT), and oncolytic virotherapies. However, most chemotherapeutic reagents are inefficient or fail to trigger ICD. Therefore, better understanding on the molecular determinants of chemotherapy-induced ICD will help in the development of more efficient combinational anticancer strategies through converting non- or relatively weak ICD inducers into bona fide ICD inducers. In this study, we found that sequential, but not concurrent, treatment of cancer cells with interferon β (IFNβ), a type I IFN, and cisplatin (an inefficient ICD inducer) can enhance the expression of ICD biomarkers in cancer cells, including surface translocation of an endoplasmic reticulum (ER) chaperone, calreticulin (CRT), and phosphorylation of the eukaryotic translation initiation factor alpha (eIF2α). These results suggest that exogenous IFNβ may activate molecular determinants that convert cisplatin into an ICD inducer. Further bioinformatics and in vitro experimental analyses found that interferon regulatory factor 1 (IRF1) acted as an essential mediator of surface CRT exposure by sequential IFNβ-cisplatin combination. Our findings not only help to design more effective combinational anticancer therapy using IFNβ and cisplatin, but also provide a novel insight into the role of IRF1 in connecting the type I IFN responses and ICD.

Clinical pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation

Isocitrate dehydrogenase (IDH) mutations lead to formation of the oncometabolite 2-hydroxyglutarate (2-HG), which is elevated in several solid and liquid tumors. Ivosidenib (AG-120) is a targeted, potent, oral inhibitor of the mutant IDH1 protein. We describe detailed pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation treated in a phase I study (ClinicalTrials.gov NCT02074839). Patients received single and multiple oral doses of ivosidenib from 100mgtwice daily to 1200mg once daily (QD) in 28-day continuous cycles. Concentrations of ivosidenib and 2-HG in plasma, and 2-HG in bone marrow, were assessed at routine intervals. Plasma 4β-hydroxycholesterol/cholesterol ratios were assessed as a marker of CYP3A activity. Ivosidenib was rapidly absorbed and slowly eliminated (half-life 72-138h) after single and multiple dosing. Ivosidenib exhibited dose- and time-dependent pharmacokinetics, with exposure increasing sub-proportionally to dose, and clearance increasing with increasing dose. Plasma 2-HG concentrations were maximally and persistently inhibited in the majority of patients receiving 500-mg QD ivosidenib, to concentrations close to those observed in healthy subjects. Ivosidenib pharmacokinetics were not affected by mild or moderate renal impairment, mild hepatic impairment, age, weight, sex, race, or co-administration of weak CYP3A4 inhibitors or inducers. Moderate-to-strong CYP3A4 inhibitors decreased ivosidenib clearance. Ivosidenib also induced CYP3A enzyme activity, with increases in 4β-hydroxycholesterol/cholesterol ratios of 119-168% at 500-mg QD ivosidenib. Ivosidenib 500-mg QD has favorable pharmacokinetic and pharmacodynamic profiles in patients with advanced hematologic malignancies with an IDH1 mutation. ClinicalTrials.gov NCT02074839.

TWEAK Promotes the Proliferation of Squamous Cell Carcinoma Cells Through Activating cIAP1 Signals.

Recent studies showed that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) induces the proliferation of squamous cell carcinoma (SCC) cells. However, the precise mechanism underlying such effect of TWEAK remains unclear. This study was designed to elucidate the role of cellular inhibitor of apoptosis 1 (cIAP1) in TWEAK-induced proliferation of SCC cells. Human SCC cells (SCC-13, A431, and SCC-9) were cultured in vitro, receiving the stimulation of TWEAK or TNF-related apoptosis-inducing ligand (TRAIL). We found that TWEAK induced cytoplasmic cIAP1 importation and RIP1 ubiquitination in cells, followed by the activation of canonical nuclear factor kappa B signals. MV1, a cIAP1 inhibitor, abrogated TWEAK-induced proliferation of these cells. Moreover, the interaction between TWEAK and its receptor, fibroblast growth factor-inducible 14 (Fn14), enhanced the expression of TRAIL receptor types 3 and 4 (TRAIL-R3/4). Furthermore, the transfection of TRAIL-R3/4 siRNA abrogated the promotion effect of TWEAK on SCC-13 cell proliferation and cIAP1 expression. Therefore, TWEAK/Fn14 interaction promotes the proliferation of SCC cells through activating cIAP1 signals. Targeting the downstream cIAP1 signals might attenuate the effect of TWEAK on SCC cells.

Lower Circulating Levels of Soluble TNF-Like Weak Inducer of Apoptosis and Chromium in Treated Brucella Infection

Brucellosis is a common infectious disease around the globe. The aim of the present investigation was to evaluate the effect of brucellosis on the serum levels of chromium (Cr), lead (Pb), soluble TNF–like weak inducer of apoptosis (sTWEAK) as well as high-sensitivity C-reactive protein (hs-CRP) and homocysteine in patients suffering from brucellosis. The present case-control study was executed on 40 treated brucellosis patients (case) and 40 healthy individuals (control). Blood samples were obtained from all the participants for the measurement of the desired indices. The serum levels of chromium in the case group (0.109±0.025 μg/L) was significantly lower compared with that in the control group (0.121±0.027 μg/L, P=0.047). The levels of lead in serum were almost unchanged between the two groups (12.58±1.94 vs. 12.28±2.42 μg/dL, P=0.533). The sTWEAK levels were significantly lower in the case group as compared to the control subjects (235.20±48.45 pg/mL vs. 262.00±67.25 pg/mL, P=0.044). The levels of hs-CRP were significantly higher in the case group (2.23±0.34 mg/L) than that in the control group (2.05±0.32 mg/L, P=0.016); similarly, homocysteine levels were higher in the serum of patients in case group as compared to the control ones (16.18±4.47 µmol/L vs. 14.36±3.06 µmol/L, P=0.038). The current investigation underlined that brucellosis causes alterations in serum chromium and sTWEAK levels, the markers that are considered as the predictors of cardiovascular disease.

Inhibition of suppressor of cytokine signaling 1 mediates the profibrotic effect of TWEAK/Fn14 signaling on kidney cells

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) engagement with the receptor Fn14 contributes to the fibrotic process of kidney cells in systemic lupus erythematosus. Downregulation of the protein suppressor of cytokine signaling 1 (SOCS1) correlates with amplified production of proinflammatory factors and cell apoptosis, which participate in the pathogenesis of lupus nephritis. To elucidate the potential role of SOCS1 in TWEAK/Fn14 signaling, we determined the SOCS1 levels in primary kidney cells from MRL/MpJ (control strain) or MRL/lpr (lupus-prone) mice. These cells (mesangial cells, glomerular endothelial cells, and tubular epithelial cells) were also evaluated after stimulation with TWEAK (0 to 250 ng/mL). The results showed that the lupus-prone cells exhibited reduced SOCS1 expression. TWEAK induced the production of profibrotic factors (laminin, fibronectin, (CC motif) ligand 20, etc.) in kidney cells from both mouse strains. TWEAK stimulation also decreased both the mRNA and protein levels of SOCS1 in all cells. Moreover, the effect of TWEAK on mesangial cells was amplified by pre-transfection of SOCS1 siRNA but was partly reduced with SOCS1 overexpression by adenoviral delivery. Therefore, TWEAK/Fn14 activation contributes to renal fibrosis in lupus nephritis involving the depression of SOCS1 function.

Controversies in TWEAK-Fn14 signaling in skeletal muscle atrophy and regeneration.

Skeletal muscle is one of the largest functional tissues in the human body; it is highly plastic and responds dramatically to anabolic and catabolic stimuli, including weight training and malnutrition, respectively. Excessive loss of muscle mass, or atrophy, is a common symptom of many disease states with severe impacts on prognosis and quality of life. TNF-like weak inducer of apoptosis (TWEAK) and its cognate receptor, fibroblast growth factor-inducible 14 (Fn14) are an emerging cytokine signaling pathway in the pathogenesis of muscle atrophy. Upregulation of TWEAK and Fn14 has been described in a number of atrophic and injured muscle states; however, it remains unclear whether they are contributing to the degenerative or regenerative aspect of muscle insults. The current review focuses on the expression and apparent downstream outcomes of both TWEAK and Fn14 in a range of catabolic and anabolic muscle models. Apparent changes in the signaling outcomes of TWEAK-Fn14 activation dependent on the relative expression of both the ligand and the receptor are discussed as a potential source of divergent TWEAK-Fn14 downstream effects. This review proposes both a physiological and pathological model of TWEAK-Fn14 signaling. Further research is needed on the switch between these states to develop therapeutic interventions for this pathway.

Pentraxin 3 (PTX3): A Molecular Marker of Endothelial Dysfunction in Chronic Migraine.

Even though endothelial dysfunction is known to play a role in migraine pathophysiology, studies regarding levels of endothelial biomarkers in migraine have controversial results. Our aim was to evaluate the role of pentraxin 3 (PTX3) and soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) as potential biomarkers of endothelial dysfunction in chronic migraine (CM). We performed a case-control study including 102 CM patients and 28 control subjects and measured serum levels of markers of endothelial dysfunction (PTX3 and sTWEAK) and inflammation [high-sensitivity C-reactive protein (hs-CRP)] as well as brachial artery flow-mediated dilation (FMD) during interictal periods. Interictal serum levels of PTX3 and sTWEAK were higher in CM patients than in controls (1350.6 ± 54.8 versus 476.1 ± 49.4 pg/mL, p < 0.001 and 255.7 ± 21.1 versus 26.4 ± 2.6 pg/mL, p < 0.0001; respectively). FMD was diminished in CM patients compared to controls (9.6 ± 0.6 versus 15.2 ± 0.9%, p < 0.001). Both PTX3 and sTWEAK were negatively correlated with FMD (r = −0.508, p < 0.001 and r = −0.188, p = 0.033; respectively). After adjustment of confounders, PTX3 remained significantly correlated to FMD (r = −0.250, p = 0.013). Diagnosis of CM was 68.4 times more likely in an individual with levels of PTX3 ≥ 832.5 pg/mL, suggesting that PTX3 could be a novel biomarker of endothelial dysfunction in CM.

Physiological Properties of Platelets in Newborn Calves of the Kholmogory Breed

The platelet activity in newborn calves of the Kholmogory breed was assessed. The studies were conducted on 39 animals obtained from healthy cows of 2–3 calving. Calves were examined five times in 2 days during the observation period. A tendency towards an increase in the activity of the aggregation process of blood platelets with all tested inducers was revealed during the neonatal phase. It was noted that the number of discoid platelets in the calf blood tended to decrease during the observation period. In these conditions, the level of activated platelets increased by 12.9% in total and the content of freely circulating aggregates of small, medium, and large sizes increased. These changes were provided in the calves by a slightly increased synthesis of thromboxane in blood platelets, which was due to the increased activity of platelet cyclooxygenase and thromboxane synthetase. In addition, a large role in the increase in platelet activity was played by growth in the quantitative content of adenosine phosphates in platelet granules and some increase in their secretion. The level of actin and myosin in calf discoid platelets during the neonatal phase increased by 6.4 and 12.6%, respectively. This was accompanied by a tendency towards growth in the amount of actin and myosin in platelets during their aggregation in response to a weak and strong inducer by 6.4 and 10.1%, respectively. The calves of the Kholmogory breed are characterized by a slightly increased activity of the hemostatic properties of platelets during the neonatal period, which eliminates their risk of bleeding under optimal conditions for microcirculation. The increasing intravascular platelet activity forms the conditions for optimal anabolic processes in tissues of animals in the neonatal period.

Fibroblast growth factor-inducible 14 mediates macrophage infiltration in heart to promote pressure overload-induced cardiac dysfunction

AimsHeart failure (HF) is characterized by compromised cardiac structure and function. Previous work has identified a link between upregulation of pro-inflammatory cytokines and HF. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a pro-inflammatory cytokine, which binds to fibroblast growth factor inducible 14 (Fn14), a ubiquitously expressed cell-surface receptor. The objective of this study was to investigate the role of TWEAK/Fn14 pathway in promoting cardiac inflammation under non ischemic stress conditions. Main methodsWild type (WT) and Fn14 knock out (Fn14−/−) mice were subjected to pressure overload [transaortic constriction (TAC)] for 1 or 6 weeks. A subset of WT TAC animals were treated with the Fn14 antagonist L524-0366. Cardiac function was measured by echocardiography. Cardiac fibrosis and macrophage infiltration were quantified using immunohistochemistry and flow cytometry, respectively. Cardiac fibroblasts were isolated for quantifying TWEAK-induced chemokine release. Key findingsFn14−/− mice displayed improved cardiac function, reduced fibrosis and lower macrophage infiltration in heart compared to WT following TAC. L524-0366 mitigated maladaptive remodeling with TAC. TWEAK induced secretion of the pro-inflammatory chemokine, monocyte chemoattractant protein 1 from WT but not Fn14−/− fibroblasts in vitro, in part through activation of non-canonical NF-κB signaling. Finally, Fn14 expression was increased in mouse following TAC and in human failing hearts. SignificanceOur findings support an important role for the TWEAK/Fn14 promoting macrophage infiltration and fibrosis in heart under non-ischemic stress, with potential for therapeutic intervention to improve cardiac function in the setting of HF.

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK)/Fibroblast Growth Factor-Inducible 14 (Fn14) Axis in Cardiovascular Diseases: Progress and Challenges.

Cardiovascular diseases (CVD) are the leading cause of mortality in Western countries. CVD include several pathologies, such as coronary artery disease, stroke, peripheral artery disease, and aortic aneurysm, among others. All of them are characterized by a pathological vascular remodeling in which inflammation plays a key role. Interaction between different members of the tumor necrosis factor superfamily and their cognate receptors induce several biological actions that may participate in CVD. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its functional receptor, fibroblast growth factor-inducible 14 (Fn14), are abundantly expressed during pathological cardiovascular remodeling. The TWEAK/Fn14 axis controls a variety of cellular functions, such as proliferation, differentiation, and apoptosis, and has several biological functions, such as inflammation and fibrosis that are linked to CVD. It has been demonstrated that persistent TWEAK/Fn14 activation is involved in both vessel and heart remodeling associated with acute and chronic CVD. In this review, we summarized the role of the TWEAK/Fn14 axis during pathological cardiovascular remodeling, highlighting the cellular components and the signaling pathways that are involved in these processes.

Serum and urine TNF-like weak inducer of apoptosis, monocyte chemoattractant protein-1 and neutrophil gelatinase-associated lipocalin as biomarkers of disease activity in patients with systemic lupus erythematosus.

TNF-like weak inducer of apoptosis (TWEAK), monocyte chemoattractant protein-1 (MCP-1) and neutrophil gelatinase-associated lipocalin (NGAL) are proinflammatory cytokines/chemokines that are considered as potential biomarkers reflecting disease activity in systemic lupus erythematosus (SLE). In this study, we aimed to investigate the association of serum (s) and urine (u) levels of TWEAK, MCP-1 and NGAL with disease activity in both renal and extra-renal SLE. Thirty active patients with SLE (15 renal and 15 extra-renal) were recruited. Thirty-one inactive patients with SLE (16 renal and 15 extra-renal), 14 patients with ANCA-associated vasculitis (AAV) all of whom had active renal involvement and 20 healthy volunteers were selected as control groups. Serum and urine levels of TWEAK, MCP-1 and NGAL were tested using ELISA. Serum and urine levels of TWEAK and NGAL were significantly higher in the active SLE group compared to the inactive SLE group (sTWEAK p = 0.005; uTWEAK p = 0.026; sNGAL p < 0.001; uNGAL p = 0.002), whilst no significant differences regarding serum and urine MCP-1 levels were observed (p = 0.189 and p = 0.106, respectively). uTWEAK (p = 0.237), sMCP-1 (p = 0.141), uMCP-1 (p = 0.206), sNGAL (p = 0.419) and uNGAL (p = 0.443) levels did not differ between patients with active renal and extra-renal SLE. Serum TWEAK was higher in patients with active renal SLE (p = 0.006). There were no differences between active renal SLE and active renal AAV. Levels of all biomarkers were correlated with the SLE Disease Activity Index. sTWEAK, uTWEAK, sNGAL and uNGAL are biomarkers showing disease activity in SLE. However, our results implicate that these biomarkers may not be specific for SLE, and can be elevated in patients with active renal involvement of AAV.

Urinary Tumor Necrosis Factor-Like Weak Inducer of Apoptosis as a Biomarker for Diagnosis and Evaluating Activity in Lupus Nephritis: A Meta-analysis.

Urinary tumor necrosis factor-like weak inducer of apoptosis (uTWEAK) has been identified as a candidate biomarker for lupus nephritis (LN). However, its diagnostic value remains unclear. This meta-analysis was conducted to comprehensively evaluate the value of uTWEAK for diagnosis and evaluating activity in LN. Medline, Web of Science, Chinese Biomedical Medical, and Chinese National Knowledge Infrastructure databases were searched to acquire eligible studies published before September 30, 2019. The quality of the studies was evaluated by Quality Assessment of Diagnostic Accuracy Studies-2. Summary receiver operating characteristic curve and area under the curve were applied to summarize the overall diagnostic performances. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated with the fixed-effects model. RevMan 5.3, Stata 12.0, and Meta-disc 1.4 software were used. A total of 7 studies were included. Of these, 4 studies were available for comparison between SLE with and without LN, and 3 studies were for active and inactive LN. The total area under the curve was 0.8640, and DOR was 14.89 (95% confidence interval [CI], 7.95-27.86). For LN diagnosis, the pooled sensitivity, specificity, and DOR were 0.55 (95% CI, 0.47-0.63), 0.92 (95% CI, 0.86-0.96), and 16.54 (95% CI, 7.57-36.15), respectively. For assessing LN activity, the pooled sensitivity, specificity, and DOR were 0.91 (95% CI, 0.82-0.96), 0.70 (95% CI, 0.58-0.81), and 18.45 (95% CI, 7.45-45.87), respectively. This meta-analysis indicated that uTWEAK has relatively moderate sensitivity and specificity for diagnosis and evaluating activity in LN, suggesting that uTWEAK can serve as a helpful biomarker for LN.

Clinical significance of urinary tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in immunoglobulin A nephropathy .

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes. Recently, it was reported that TWEAK may play an important role in the pathogenesis of kidney damage. In the present study, we investigated the role of TWEAK in immunoglobulin A nephropathy (IgAN). The levels of serum TWEAK (sTWEAK) and urinary TWEAK (uTWEAK) in 45 patients with IgAN and 15 healthy subjects were measured. We analyzed the correlations of uTWEAK level with clinical and pathological parameters in patients with IgAN. We then divided the patients into two groups according to uTWEAK level and investigated 5-year chronic kidney disease (CKD) progression. The level of uTWEAK was significantly higher in patients with IgAN than in healthy controls (p<0.001). sTWEAK level showed no significant difference between the two groups (p=0.225). The level of uTWEAK correlated significantly with serum albumin (p<0.001), urine protein excretion (p<0.001), and histological classification (p<0.016) in patients with IgAN. uTWEAK was significantly increased even in patients with IgAN who had lower proteinuria. There was a significant association between uTWEAK level and CKD progression (p=0.049). Although uTWEAK is not a superior biomarker compared to proteinuria, it has a significant correlation with IgAN patients and seems to be useful in determining disease progression.

MicroRNA-1 Negatively Regulates Peripheral NK Cell Function via Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Signaling Pathways During PPRV Infection.

Peste des petits ruminants virus (PPRV) has emerged as a significant threat to the productivity of small ruminants worldwide. PPRV is lymphotropic in nature and induces in the hosts a transient but severe immunosuppression, especially innate immunity. However, it remains largely unknown how NK cells respond and are regulated at the earliest time points after an acute viral PPRV infection in goats. In this study, we revealed that multiple immune responses of goat peripheral NK cells were compromised during PPRV infection, including the cytolytic effector molecule expression and cytokine production. Importantly, we demonstrated that PPRV infection stimulated the expression of TWEAK, a negative regulator of cytotoxic function of NK cells, which may be involved in the suppression of cytotoxicity as well as cytokine production in infected goat NK cells. Furthermore, we found that PPRV infection induced TWEAK expression in goat NK cells involving post-transcription by suppressing miR-1, a novel negative miRNA directly targeting the TWEAK gene. Moreover, replication of virus is required for inhibition of miR-1 expression during PPRV infection, and the non-structural V protein of PPRV plays an important role in miR-1 mediated TWEAK upregulation. Additionally, we revealed that the regulation of NK cell immune responses by TWEAK is mediated by MyD88, SOCS1, and STAT3. Taken together, our results demonstrated that TWEAK may play a key role in regulating goat peripheral NK cell cytotoxicity and cytokine expression levels during PPRV infection.