Like Weak Inducer Of Apoptosis Research Articles

Tumour necrosis factor like weak inducer of apoptosis (TWEAK) in serum and tissue of patient with psoriasis vulgaris

Tumour necrosis factor like weak inducer of apoptosis (TWEAK) in serum and tissue of patient with psoriasis vulgaris

Sarcopenia is associated with hypomethylation of TWEAK and increased plasma levels of TWEAK and its downstream inflammatory factor TNF-α in older adults: A case-control study

BackgroundSarcopenia is a harmful condition common among older adults for which no treatment is available. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor inducible 14 (FN14) are known to play important roles in the pathogenesis of sarcopenia. This study investigated alterations in methylation in TWEAK and Fn14 to identify potential targets for the managing sarcopenia. Materials and methodsThrough an epidemiological investigation, we detected methylation of CpG islands (CpGs) in TWEAK and Fn14 in community-dwelling older adult of Xinjiang by bisulfite sequencing. Significant CpGs associated with sarcopenia were selected for detection in 152 older individuals by pyrosequencing. Associations between CpG methylation, plasma inflammatory marker levels, and sarcopenia were analyzed. ResultsOf 38 CpGs in TWEAK and 30 CpGs in Fn14 detected in 60 individuals, 6 CpGs showed lower methylation in sarcopenia patients compared with control individuals. In 152 older adults, covariance analysis with adjustment for age, gender, triglyceride level, obesity, diabetes, and hypertension showed that the methylation levels of 6 CpGs (CpG8, CpG12, CpG13, CpG20 and CpG21of TWEAK, and CpG24 of Fn14) were significantly lower in sarcopenia patients than in control individuals. With adjustment for additional confounding factors, covariate variance analysis showed that plasma TWEAK, TNF-α and IL-10 levels in the sarcopenia group were significant higher than those in the control group (P = 0.007, P < 0.001, P = 0.003). Multivariate logistic regression analysis showed that CpG8, CpG13, CpG21, and total methylation of TWEAK (OR = 0.767, 95 % CI = 0.622–0.947; OR = 0.740, 95 % CI = 0.583–0.941; OR = 0.734, 95 % CI = 0.561–0.958; OR = 0.883, 95 % CI = 0.795–0.980) as well as CpG22 and total methylation of Fn14 were significantly associated with sarcopenia (OR = 826, 95 % CI = 0.704–0.968; OR = 0.918, 95 % CI = 0.852–0.989). From partial correlation analysis, plasma TWEAK was correlated with plasma TNF-α (r = 0.172, P = 0.042). ConclusionSarcopenia is associated with hypomethylation of TWEAK and increased plasma levels of TWEAK and its downstream inflammatory factor TNF-α in a community-dwelling population of older adults in Xinjiang.

Abstract B009: TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in Triple-Negative Breast Cancer

Abstract Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from a lack of targeted treatment options. There is a high priority to identify effective molecular markers or driver factors specific to TNBC patients for targeted therapies. The Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/Fibroblast growth factor-inducible 14 (Fn14) pathway is one such signalling cascade implicated in the pathogenesis of TNBC and other solid tumours. However, the clinical significance and biological roles of deregulated TWEAK/Fn14 signalling in regulating the epigenetic plasticity and transcriptome of TNBCs remain elusive. In this study, we performed integrative transcriptomic and epigenomic analyses of TNBC cell lines and patient samples to characterise the gene regulatory roles of TWEAK/Fn14 pathway in remodelling the super-enhancer (SE) landscape of TNBC tumours. Here, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of NAMPT, which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients. Citation Format: Yinghui Li, Nicholas Sim, Jean-Michel Carter, Kamalakshi Deka, Benita Kiat Tee Tan, Yirong Sim, Suet-Mien Tan. TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in Triple-Negative Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B009.

Correlation of expression of silencing information regulator 2 related enzyme 1 and tumor necrosis factor-like weak inducer of apoptosis in articular effusion and knee osteoarthritis

To analyze the correlation between the expression of silencing information regulator 2 related enzyme 1 (SIRT1), tumor necrosis factor like weak inducer of apoptosis (TWEAK) and knee osteoarthritis. Total of 103 patients with knee joint (knee osteoarthritis group) from February 2019 to August 2021 were selected including 40 males and 63 females with an average age of (62.02±6.09) years;according to the modified Mankin score, 103 patients were divided into mild group (Mankin score 1-4 points, 31 cases) and moderate group (Mankin score 5-8 points, 40 cases) and severe group (Mankin score ≥9, 32 cases). Another 105 physical examination volunteers were selected as the control group including 46 males and 59 females with an average age of (62.11±6.34) years old. The levels of SIRT1 and TWEAK in articular effusion and serum were detected in the knee osteoarthritis group, while serum SIRT1 and TWEAK were detected in the control group only. The relationship between SIRT1, TWEAK and the occurrence and disease of knee osteoarthritis were analyzed. Articular cavity fluid TWEAK, serum TWEAK, CRP, IL-6, IL-1β, white blood cell count and ESR were higher than those in the control group(P<0.05), articular cavity fluid SIRT1 and serum SIRT1 were lower than those in the control group(P<0.05). TWEAK level in the severe group was higher than that in the moderate and mild groups(P<0.05), SIRT1 was lower than that in the moderate and mild groups (P<0.05). The level of SIRT1 in articular cavity effusion was positively correlated with the serum level of SIRT1 (P<0.05), and negatively correlated with CRP, IL-6, IL-1β, white blood cell count, modified Mankin score and ESR (P<0.05). TWEAK level in articular cavity fluid was positively correlated with serum TWEAK level (P<0.05), C-reactive protein(CRP), interleukin(IL)-6, IL-1β, white blood cell count, modified Mankin score and erythrocyte sedimentation rate(ESR) (P<0.05). Body mass index, undertaking heavy physical work, and articular cavity fluid TWEAK were risk factors for the occurrence of knee osteoarthritis(P<0.05), and articular cavity fluid SIRT1 was a protective factor for the occurrence of knee arthritis (P<0.05). The area under curve(AUC) of SIRT1 and TWEAK for knee osteoarthritis was 0.641 and 0.653, and the AUC of SIRT1 and TWEAK for knee osteoarthritis was 0.879, which was higher than SIRT1 and TWEAK alone (z=6.105 and 6.225, P<0.05). The level of SIRT1 in articular fluid in patients with knee arthritis is decreased and the level of TWEAK is increased. Low SIRT1 and high TWEAK are associated with the onset and exacerbation of knee osteoarthritis.

Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity.

Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFκB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcγ receptors (FcγR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcγR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcγR-independent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFκB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFκB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFκB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK.

TWEAK Progress in Dermatology: A Review.

Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily (TNFSF). It acts through its receptor fibroblast growth factor-inducible 14 (Fn14). Studies have indicated that TWEAK/Fn14 pathway activation controls multiple cellular responses, including proliferation, angiogenesis and induction of inflammatory cytokines. TWEAK/Fn14 is manifested in many tissues of our body and most importantly in the skin causing inflammation and many autoimmune and neoplastic cutaneous disorders. Evidence suggests that the TWEAK/Fn14 axis, the downstream signalling pathway and its inflammatory molecular expressions are involved in the pathogenesis of many cutaneous disorders such as psoriasis, atopic dermatitis (AD) vitiligo and melanoma. So, this literature review describes a brief introduction of TWEAK and TWEAK/Fn14 pathway and summarises the case-series and open-label studies performed in the field of dermatology and its potential therapeutic benefit.

Lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of prostate carcinogenesis

This work aimed to understand how lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of PCa. Fifty-five male Wistar rats were divided into four groups: control sedentary, control exercised, induced PCa sedentary and induced PCa exercised. Exercised animals were trained in a treadmill for 53 weeks. Pca induction consisted on the sequential administration of flutamide, N-methyl-N-nitrosourea and testosterone propionate implants. Serum concentrations of C-reactive protein (CRP) and tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) were not different among groups. Peripheral levels of γδ T cells were higher in Pca exercised group than in the PCa sedentary group (p < 0.05). Exercise training also induced Oestrogen Receptor (ESR1) upregulation and Mitogen-activated Protein Kinase 13 (MAPK13) downregulation, changed the content of the phosphorylated (at Ser-104) form of this receptor (coded by the gene ESR1) and seemed to increase Erα phosphorylation and activity in exercised PCa rats when compared with sedentary PCa rats. Our data highlight the exercise-induced remodelling of peripheral lymphocyte subpopulations and lymphocyte infiltration in prostate tissue. Moreover, exercise training promotes the remodelling prostate signalome in this rat model of prostate carcinogenesis.

TWEAK/Fn14 Signalling Regulates the Tissue Microenvironment in Chronic Pancreatitis

Chronic pancreatitis increases the risk of developing pancreatic cancer through the upregulation of pathways favouring proliferation, fibrosis, and sustained inflammation. We established in previous studies that the ligand tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) signals through its cognate receptor fibroblast growth factor-inducible 14 (Fn14) to regulate these underlying cellular processes in the chronic liver injury niche. However, the role of the TWEAK/Fn14 signalling pathway in pancreatic disease is entirely unknown. An analysis of publicly available datasets demonstrated that the TWEAK receptor Fn14 is upregulated in pancreatitis and pancreatic adenocarcinoma, with single cell RNA sequencing revealing pancreatic ductal cells as the main Fn14 producers. We then used choline-deficient, ethionine-supplemented (CDE) diet feeding of wildtype C57BL/6J and Fn14 knockout littermates to (a) confirm CDE treatment as a suitable model of chronic pancreatitis and (b) to investigate the role of the TWEAK/Fn14 signalling pathway in pancreatic ductal proliferation, as well as fibrotic and inflammatory cell dynamics. Our time course data obtained at three days, three months, and six months of CDE treatment reveal that a lack of TWEAK/Fn14 signalling significantly inhibits the establishment and progression of the tissue microenvironment in CDE-induced chronic pancreatitis, thus proposing the TWEAK/Fn14 pathway as a novel therapeutic target.

Abstract 3129: TWEAK cytokine supports ovarian cancer tumor-initiating cell (TIC) phenotypes important for relapse

Abstract Ovarian cancer is the deadliest gynecological cancer with over 13,000 deaths estimated in the United States this year. While there is an initial high response rate to cytotoxic chemotherapy, over 80% of advanced cases relapse within 24 months, presenting an urgent need to better understand the molecular mechanisms permitting relapse. Current research suggests that cancer recurrence can be attributed to a small subpopulation of cancer stem-like tumor-initiating cells (TICs) that possess the ability to both resist chemotherapy and initiate tumorigenesis. Our lab previously demonstrated an essential role for alternative NF-kB signaling in maintaining ovarian TICs, yet it is not fully understood how this pathway becomes activated in ovarian cancer. To begin to address this, we used an NF-kB reporter system to screen soluble factors known to be in the ovarian tumor microenvironment (TME) to identify the strongest inducers of NF-kB activation in ovarian cancer cells. We found that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a strong inducer of alternative NF-kB signaling. In vitro experiments demonstrate enhanced expression of stemness genes including SOX2, OCT4 and NANOG and increased spheroid formation ability after stimulation with TWEAK. Moreover, flow cytometry analysis of several TIC markers shows a significant enrichment of TICs when chemotherapy was combined with TWEAK, relative to chemotherapy alone. Stimulation of CD117+ cells led to higher expression of stemness genes relative to stimulation of CD117- cells, suggesting TWEAK activity may be specific to TICs and enhances their stem-like phenotype. In support of this, we found that CD117+ cells have higher expression of the TWEAK receptor FN14. We investigated the role of TWEAK in aiding relapse in vivo using an intraperitoneal xenograft mouse model and found that administration of a small molecule inhibitor of TWEAK-FN14 signaling as a maintenance treatment following chemotherapy significantly prolonged survival. These findings highlight a potential mechanism of TIC enrichment in response to chemotherapy that contributes to relapse. Citation Format: Denay N. Stevenson, Ryne M. Holmberg, Samuel F. Gilbert, Mikella Robinson, Carrie D. House. TWEAK cytokine supports ovarian cancer tumor-initiating cell (TIC) phenotypes important for relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3129.

Lower Expression of TWEAK is Associated with Poor Survival and Dysregulate TIICs in Lung Adenocarcinoma.

Background Lung cancer remains the leading cause of cancer death worldwide, and the most subtype is lung adenocarcinoma (LUAD). Tumor-infiltrating immune cells (TIICs) greatly impact the prognosis of LUAD. Tumor necrosis factor–like weak inducer of apoptosis (TWEAK), signal via its receptor fibroblast growth factor-inducible 14 (Fn14), dysregulates immune cell recruitment within tumor environment, thus promoting the progression of autoimmune diseases and cancer. We aimed to explore its role in LUAD. Methods The expression level of TWEAK was explored in Tumor Immune Estimation Resource 2.0 (TIMER2.0) and Oncomine databases. The Tumor Immune Dysfunction and Exclusion (TIDE) and Lung Cancer Explorer (LCE) databases were applied to evaluate the survival in correlation to TWEAK expression. TIICs were assessed with TIMER2.0 and TIDE datasets. The expression of TWEAK protein was detected in LUAD cell lines and also in tissue samples from LUAD patients via western blotting or combination with immunochemistry. Results Our results showed that TWEAK was downregulated in LUAD tumors compared to normal tissues in TIMER2.0, Oncomine, cell lines, and clinical specimens. Poor survival was uncovered in lower TWEAK expression of LUAD patients in LCE (meta − HR = 0.84 [95% CI, 0.76-0.92]) and TCGA (Continuous Z = −1.97, p = 0.0486) and GSE13213@PRECOG (Continuous Z = −4.25, p = 2.12e − 5) in TIDE. Multiple tumor-infiltrating immune cells (TIICs) were found closely correlated with TWEAK expression in LUAD, especially hematopoietic stem cell (Rho = 0.505, p = 2.78e − 33), common lymphoid progenitor (Rho = −0.504, p = 3.79e − 33), and myeloid-derived suppressor cells (MDSCs) (Rho = −0.615, p = 1.36e − 52). Conclusion Lower level of TWEAK was linked with poor survival and aberrant recruitment and phenotype of TIICs in LUAD, which might motivate immune escape and weaken the effects of immunotherapy.

“Therapeutic targeting of tumor necrosis factor like weak inducer of apoptosis (TWEAK) in psoriasis”

Abstract Excessive activity of TNF and IL-17 in keratinocytes can drive psoriatic skin inflammation and their targeting is highly advantageous in psoriasis patients, but whether these cytokines act with other inflammatory molecules is unknown. Previously, we demonstrated with knockout mice that the TNF-related cytokine TWEAK (TNFSF12) was a major driver of skin inflammation in the imiquimod model of psoriasis. Here, we found that mice carrying a deletion of TWEAK’s receptor, Fn14 (TNFRSF12A), specifically in keratinocytes, exhibited reduced psoriasis features, including less epidermal hyperplasia and poor expression of genes associated with human psoriasis. Further, RNA-seq analysis in human keratinocytes demonstrated that TWEAK strongly synergizes with either TNF or IL-17A in upregulating the transcripts for psoriasis-associated chemokines and cytokines, implying that TWEAK co-operates with TNF and IL-17 to enhance feedback inflammatory activity. Correspondingly, administration of anti-TWEAK antibody demonstrated therapeutic efficacy in the psoriasis mouse model and was equally as effective as antibodies to IL-17A or TNF in reducing clinical and immunological features of psoriasis-like skin inflammation, while co-neutralization of TWEAK with either cytokine had no additional therapeutic effect, reinforcing the conclusion that all three cytokines act together. We conclude that TWEAK blockade could be another potential therapeutic avenue in patients with psoriasis that might be equally as useful as blocking TNF and IL-17. Future studies targeting TWEAK in clinical trials for psoriasis may then be warranted. Supported by NIH grant AR072640

Circulating sTweak is associated with visceral adiposity and severity in patients with obstructive sleep apnea syndrome

Hypoxia is linked to an inflammatory imbalance in obstructive sleep apnea syndrome (OSAS). Circulating soluble tumor necrosis factor (TNF)-like weak inducer of apoptosis (sTWEAK) is a cytokine that regulates inflammation and insulin resistance in adipose tissue. This study first investigated sTWEAK concentrations in patients OSAS and evaluated associations between sTWEAK concentrations and visceral adiposity, metabolic dysfunction, and hypoxia observed in OSAS. Forty age, sex, and body mass index-matched patients with simple habitual snoring (HSS) and 70 patients with OSAS were included. Patients were divided according to OSAS severity: mild-moderate (apnea–hypopnea index, AHI 5–30 events/h) and severe (AHI ≥ 30 events/h). Anthropometric data, glucose metabolism, visceral fat (VF) ratio, and sTWEAK levels were compared. sTWEAK levels were higher in the OSAS group than in the HSS group (931.23 ± 136.48 vs. 735.22 ± 102.84 ng/L, p = 0.001). sTWEAK levels were higher in severe OSAS than in mild-moderate OSAS (1031.83 ± 146.69 vs. 891.01 ± 110.01 ng/L, p = 0.002. When we evaluated the sTWEAK value and AHI, VF ratio, total cholesterol, blood pressure, homeostasis model of assessment-insulin resistance, and high-sensitivity C-reactive protein using multiple regression analysis, a significant correlation was found between sTWEAK levels and AHI (p < 0.001). It was found that sTWEAK levels were not correlated with glucose metabolism and VF ratio. Increased circulating sTWEAK levels were associated with the severity of OSAS. High sTWEAK levels were correlated with increased AHI. sTWEAK concentrations are linked to severe OSAS.

Pro-Inflammatory and B Cell Regulating Capacities of TWEAK in Rainbow Trout (Oncorhynchus mykiss).

Tumor necrosis factor (TNF)-like weak inducer of apoptosis or TWEAK is a member of the TNF superfamily involved in the regulation of many biological processes. In mammals, TWEAK has been shown to play a role in some autoimmune or inflammatory conditions, but its immune role is not yet clearly defined. In teleost fish, although a few studies have identified homologues to mammalian TWEAK, their biological effects have never been investigated. In the current study, we have studied the transcriptional regulation of two TWEAK homologues (TWEAK 1 and 2) identified in rainbow trout (Oncorhynchus mykiss) throughout different tissues, in response to parasitic or viral infections, or in head kidney (HK) leukocytes stimulated with different stimuli. Although the transcription of both homologues was modulated when HK leukocytes were exposed to several immune stimuli, only TWEAK 1 was significantly modulated upon pathogenic exposure. Thus, we performed a characterization of the functions exerted by this cytokine in HK leukocytes. Recombinant TWEAK 1 strongly up-regulated the transcription of pro-inflammatory genes and antimicrobial peptides in HK leukocytes, with differential transcriptional effects in IgM+ B cells, IgM- lymphocytes and myeloid cells. TWEAK 1 also increased the survival and promoted the differentiation of B cells in HK leukocyte cultures. Our results demonstrate that in teleost fish, TWEAK 1 is involved in the response to different types of pathogens, through the modulation of antimicrobial and pro-inflammatory genes in different leukocytes subsets. Furthermore, a role for TWEAK as a B cell differentiation factor has also been established in rainbow trout.

Remodeling of Neurotransmission, Chemokine, and PI3K-AKT Signaling Genomic Fabrics in Neuropsychiatric Systemic Lupus Erythematosus.

Cognitive dysfunction and mood changes are prevalent and especially taxing issues for patients with systemic lupus erythematosus (SLE). Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its cognate receptor Fn14 have been shown to play an important role in neurocognitive dysfunction in murine lupus. We profiled and compared gene expression in the cortices of MRL/+, MRL/lpr (that manifest lupus-like phenotype) and MRL/lpr-Fn14 knockout (Fn14ko) adult female mice to determine the transcriptomic impact of TWEAK/Fn14 on cortical gene expression in lupus. We found that the TWEAK/Fn14 pathway strongly affects the expression level, variability and coordination of the genomic fabrics responsible for neurotransmission and chemokine signaling. Dysregulation of the Phosphoinositide 3-kinase (PI3K)-AKT pathway in the MRL/lpr lupus strain compared with the MRL/+ control and Fn14ko mice was particularly prominent and, therefore, promising as a potential therapeutic target, although the complexity of the transcriptomic fabric highlights important considerations in in vivo experimental models.

Assessment of serum TWEAK levels in patients with familial Mediterranean fever

Background/Aim: Mediterranean fever is an autoinflammatory disease characterized by recurrent attacks. Tumor necrosis factor (TNF) - like weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family, and it has been reported to contribute significantly to the initiation of many inflammatory and immunological processes. In previous studies, an increasing amount of evidence has implicated the participation of TWEAK / Fn14 pathway in the pathogenesis of rheumatic inflammatory diseases that include rheumatoid arthritis, systemic lupus erythematosus and Behçet's disease. The aim of this study was to investigate the serum TWEAK levels of patients with Familial Mediterranean fever (FMF) and its possible relationship with inflammatory markers and disease activity. Methods: Our study included 20 patients with FMF and 19 healthy volunteers. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) were measured, and PRAS disease severity score was determined in patients with FMF. Also, the FMF attack period was questioned. Serum TWEAK levels were measured with available commercial Enzyme Linked Immunosorbent Assay kits. Results: There was no significant difference in terms of age and gender between the FMF group and the healthy control group (P>0.05, for all). ESR, CRP and serum TWEAK levels were significantly higher in patients with FMF (P<0.001 for all). PRAS score in FMF patients was 3.4. Serum TWEAK level was not correlated with ESR (r=-0.042, P=0.0801), CRP (r=-0.017 P=0.921), or PRAS score (r=0.247, P=0.149). The ESR and CRP levels of patients in FMF attack period were significantly higher compared to attack free period (P<0.001 for both) whereas there was no significant difference in serum TWEAK levels (P=0.686). Conclusions: Serum TWEAK levels are increased in FMF disease with attacks. However, this increase is not associated with increased ESR and CRP during FMF attacks. These results indicate that the TWEAK / Fn14 pathway plays a role in earlier stages where the inflammatory pathways have not differentiated yet. Serum TWEAK levels appear to be more successful in reflecting a lower degree of inflammation compared to ESR and CRP.

Diagnostic value of TWEAK for predicting active lupus nephritis in patients with systemic lupus erythematosus: a systematic review and meta-analysis

Purpose Accumulative studies showed that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) was up-regulated in the blood and urine from patients diagnosed with lupus nephritis (LN) and that it might be used as a novel biomarker for active LN. This meta-analysis aimed to determine the diagnostic value of TWEAK in active LN. Methods We searched the Cochrane Library, Embase, PubMed, Springer, Wanfang and CNKI databases for articles published up to 20 August 2020. The diagnostic capacity of TWEAK for active LN was assessed using pooled sensitivity and specificity, positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC). Quality assessment and publication bias were also evaluated. STATA 11.0 and Meta-Disc 1.4 were used to perform these analyses. Results Nine cross-sectional studies were included in this meta-analysis. The overall pooled sensitivity of TWEAK for the diagnosis of active LN was 0.69 (95% CI, 0.63–0.75), and specificity was 0.77 (95% CI, 0.71–0.82). The overall pooled PLR and NLR were 3.31 (95% CI, 2.05–5.35) and 0.38 (95% CI, 0.26–0.55), respectively, with a DOR of 10.89 (95% CI, 6.73–17.63) and AUC (SE) of 0.8276 (0.0289). Deeks’ funnel plot revealed that the publication bias was insignificant in the study (p = .32). Conclusions Our results suggest that TWEAK might be a potential biomarker for patients with active LN. Future cross-sectional and longitudinal studies are needed to confirm its diagnostic value, as well as to establish more definite cutoff for active LN.

Serum Levels of Tumor Necrosis Factor- Like Weak Inducer of Apoptosis (TWEAK) in Patients With Psoriasis Vulgaris

Background: Psoriasis is a chronic, immune-mediated, systemic inflammatory disease that is defined by a characteristic skin reaction produced when elevated levels of inflammatory cytokines that alter the growth and differentiation of skin cells. Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of variety of inflammatory disorders and autoimmune diseases. However, studies conducted on the relationship of TWEAK and psoriasis patients are limited. Objective: We aimed to assess the serum level of TWEAK in psoriatic patients and determine whether levels are related with clinical variables, such as disease severity and duration. Patients and Methods: The study was conducted on 30 patients with psoriasis attending Dermatology, Venerology & Andrology Outpatient Clinic, Faculty of Medicine, Zagazig University Hospitals spanning the period from January 2019 to March 2019. They were divided into mild, moderate and severe according to Psoriasis Area and Severity Index (PASI) score, 10 patients in each group. The patients' age ranged from 10 to 60 years old. 10 healthy subjects with matched age and sex served as control group. Results: There was non-significant difference between the studied groups regarding age, BMI, sex, family history, DM and smoking. However, the difference between them was highly significant regarding itching and presence of stressors. The mean TWEAK levels were significantly higher in psoriasis patients than in control subjects, which was significantly associated with severity and duration of the disease. There was positive correlation (P < 0.001) between serum TWEAK levels and severity of psoriasis with highly significant level in severe cases. Conclusion: The serum TWEAK levels significantly correlated with the clinical state, as represented by the PASI score. Also, it was found that TWEAK measurement in serum of patients with psoriasis provides a tool for monitoring disease activity and its use as a marker of disease severity. Thus, they have prognostic significance.

Serum Levels of Tumor Necrosis Factor- Like Weak Inducer of Apoptosis (TWEAK) in Patients With Psoriasis Vulgaris

Psoriasis is a chronic, immune-mediated, systemic inflammatory disease that is defined by a characteristic skin reaction produced when elevated levels of inflammatory cytokines that alter the growth and differentiation of skin cells. Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of variety of inflammatory disorders and autoimmune diseases. However, studies conducted on the relationship of TWEAK and psoriasis patients are limited.

TWEAK/Fn14 axis is an important player in fibrosis.

Fibrosis is a common pathological condition associated with abnormal repair after tissue injury. However, the etiology and molecular mechanisms of fibrosis are still not well-understood. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) belongs to the TNF superfamily and acts by binding to its receptor, fibroblast growth factor-inducible 14 (Fn14), thereby activating a variety of intracellular signal transduction pathways in various types of cells. Besides promoting the expression of growth factors, activation of TWEAK/Fn14 signaling after tissue injury can promote the expression of pro-inflammatory cytokines, which trigger the immune response, thereby exacerbating the injury. Severe or repetitive injury leads to a dysregulated tissue repair process, in which the TWEAK/Fn14 axis promotes the activation and proliferation of myofibroblasts, induces the secretion of the extracellular matrix, and regulates profibrotic mediators to further perpetuate and sustain the fibrotic process. In this review, we summarize the available experimental evidence on the underlying molecular mechanisms by which the TWEAK/Fn14 pathway mediates the development and progression of fibrosis. In addition, we discuss the therapeutic potential of the TWEAK/Fn14 pathway in fibrosis-associated diseases based on evidence derived from multiple models and cells from injured tissue and fibrotic tissue.

Advanced glycation end products (AGEs) synergistically potentiated the proinflammatory action of lipopolysaccharide (LPS) and high mobility group box-1 (HMGB1) through their direct interactions.

Previously, we found that advanced glycation endproducts (AGEs) directly interact with tumor necrosis factor (TNF)-like weak inducer of apoptosis, a cytokine that controls inflammation, and that this interaction inhibited its action. This finding raised the novel possibility that AGEs alter the function of other cytokines through direct interaction. To investigate this possibility, we performed comprehensive screening for candidates that interacted with AGEs using protein array analysis.The array analysis revealed that high mobility group box-1 (HMGB1) had a markedly high affinity for AGEs. HMGB1 is a representative proinflammatory damage-associated molecular pattern molecule, and is reported to interact with lipopolysaccharide (LPS) directly to exert its inflammatory function. When LPS, HMGB1, and AGEs were mixed, the mobility of HMGB1 had shifted significantly in native PAGE, suggesting that these three molecules formed a triplet complex. The addition of AGEs to the LPS-HMGB1 mixture synergistically potentiated LPS-HMGB1-stimulated TNF-α mRNA expression in macrophage-like RAW264.7 cells. In addition, using receptor knockout clones, the increased proinflammatory response by LPS-HMGB1-AGEs complex was demonstrated to be mediated via Toll-like receptor 4 and receptor for AGEs.Taken together, this study suggested that AGEs carry out their pathophysiological roles by potentiating the LPS-HMGB1-stimulated proinflammatory response through direct interactions.