Role Of Tumor Necrosis Factor Research Articles

Divergent effects of tumor necrosis factor (TNF) in sepsis: a meta-analysis of experimental studies

IntroductionExperimental studies in animals have yielded conflicting results on the role of Tumor Necrosis Factor (TNF) in sepsis and endotoxemia, with some reporting adaptive and others inappropriate effects. A meta-analysis of the available literature was performed to determine the factors explaining this discrepancy.MethodsThe study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol was registered with PROSPERO (CRD42020167384) prior to data collection. PubMed and Embase were the databases queried. Risk of bias was evaluated using the SYRCLE Risk of Bias Tool. All animal studies investigating sepsis-related mortality and modified TNF signaling were considered eligible. The exclusion criteria were: lack of mortality data, 7-day mortality rates below 10% in both wild type and TNF-altered pathway animals, and absence of an English abstract. To determine the role of TNF according to the experimental protocol, three approaches were used: first an approach based on the statistical significance of each experiment, then the pooled mortality was calculated, and finally the weighted risk ratio for mortality was assessed.ResultsA total of 175 studies were included in the analysis, comprising a total of 760 experiments and involving 19,899 animals. The main species used were mice (77%) and rats (21%). The most common method of TNF pathway modulation was TNF pathway inactivation that was primarily associated with an inappropriate secretion of TNF. At the opposite, TNF injection was associated with an adaptive role of TNF. Lipopolysaccharide (LPS) injection was the most used stimulus to establish an infectious model (42%) and was strongly associated with an inappropriate role of TNF. Conversely, live bacterial models, especially the cecal ligation and puncture (CLP) model, pneumonia, meningitis, and gastrointestinal infection, were associated with an adaptive role. This was particularly evident for Listeria monocytogenes, Streptococcus pneumoniae.ConclusionThe role of TNF during infection varies depending on the experimental model used. Models that mimic clinical conditions, based on virulent bacteria that cause high mortality even at low inocula, demonstrated an adaptive role of TNF. Conversely, models based on LPS or low-pathogenic live bacteria, administered at doses well above physiological thresholds and combined with early antibiotic therapy, were associated with an inappropriate role.Graphical abstract

Serum BAFF, APRIL, TWEAK, TNFSF18, TNFR2, and TNFRS12A levels in preschool children with autism spectrum disorder

Objectives A gradually increasing number of studies have reported that dysregulation in the immune system may be a contributing factor in the etiopathogenesis of autism spectrum disorder (ASD). However, only limited data has existed about the role of tumor necrosis factor (TNF) superfamily members in ASD. This study aimed to investigate whether serum levels of BAFF, APRIL, TWEAK, TNFSF18 TNFR2, and TNFRS12A are associated with ASD in preschool children. Methods A total of 65 (52 boys/13 girls) preschool children with ASD and 40 (28 boys/12 girls) healthy controls were included in the study. The severity of the ASD symptoms was assessed by the Autism Behavior Checklist and the Childhood Autism Rating Scale. Serum levels of immunologic parameters were measured by enzyme-linked immunosorbent assay. Results Analysis indicated that serum BAFF, TNFSF18, TNFR2, and TNFRS12A levels were significantly lower and serum APRIL and TWEAK levels were significantly higher in the ASD group than in the control group. However, with logistic regression only low BAFF levels and high APRIL levels had relationships with the presence of ASD. Conclusions These findings suggest that TNF superfamily members, especially the BAFF/APRIL system may play a role in the pathophysiology of ASD.

Deciphering Microbiome, Transcriptome, and Metabolic Interactions in the Presence of Probiotic Lactobacillus acidophilus against Salmonella Typhimurium in a Murine Model.

Salmonella enterica serovar Typhimurium (S. Typhimurium), a foodborne pathogen that poses significant public health risks to humans and animals, presents a formidable challenge due to its antibiotic resistance. This study explores the potential of Lactobacillus acidophilus (L. acidophilus 1.3251) probiotics as an alternative strategy to combat antibiotic resistance associated with S. Typhimurium infection. In this investigation, twenty-four BALB/c mice were assigned to four groups: a non-infected, non-treated group (CNG); an infected, non-treated group (CPG); a group fed with L. acidophilus but not infected (LAG); and a group fed with L. acidophilus and challenged with Salmonella (LAST). The results revealed a reduction in Salmonella levels in the feces of mice, along with restored weight and improved overall health in the LAST compared to the CPG. The feeding of L. acidophilus was found to downregulate pro-inflammatory cytokine mRNA induced by Salmonella while upregulating anti-inflammatory cytokines. Additionally, it influenced the expression of mRNA transcript, encoding tight junction protein, oxidative stress-induced enzymes, and apoptosis-related mRNA expression. Furthermore, the LEfSe analysis demonstrated a significant shift in the abundance of critical commensal genera in the LAST, essential for maintaining gut homeostasis, metabolic reactions, anti-inflammatory responses, and butyrate production. Transcriptomic analysis revealed 2173 upregulated and 506 downregulated differentially expressed genes (DEGs) in the LAST vs. the CPG. Functional analysis of these DEGs highlighted their involvement in immunity, metabolism, and cellular development. Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis indicated their role in tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), chemokine, Forkhead box O (FOXO), and transforming growth factor (TGF-β) signaling pathway. Moreover, the fecal metabolomic analysis identified 929 differential metabolites, with enrichment observed in valine, leucine, isoleucine, taurine, glycine, and other metabolites. These findings suggest that supplementation with L. acidophilus promotes the growth of beneficial commensal genera while mitigating Salmonella-induced intestinal disruption by modulating immunity, gut homeostasis, gut barrier integrity, and metabolism.

The Role of Tumor Necrosis Factor (TNF) Alpha with Visual Field Defects in Primary Open Angle Glaucoma (POAG)

Introduction & ObjectivesGlaucoma is a group of progressive optic neuropathy disease characterized by degeneration ofretinal ganglion cells. This causes changes in the optic nerve and loss of visual field. Several studieshave revealed that there is a role for TNF Alpha in glaucoma cases. To determine the role TumorNecrosis Factor (TNF) Alpha Levels between visual field defects in Primary Open-angle Glaucomapatients.
 MethodsThis study is Observational Analytical with cross sectional data collection method. Examination ofthe field of view using the Humphrey visual field perimetry.
 ResultsThe sample of this research was 30 people with 16 (53.3%) male and 14 people (46.7%) female.Using the Spearman correlation test, it showed that there was no significant correlation betweenTNF alpha and field of view (p = 0.119).
 ConclusionTNF Alpha level was not significantly related to visual field defects.

TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria

BackgroundExcess tumor necrosis factor (TNF) is implicated in the pathogenesis of hyperinflammatory experimental cerebral malaria (eCM), including gliosis, increased levels of fibrin(ogen) in the brain, behavioral changes, and mortality. However, the role of TNF in eCM within the brain parenchyma, particularly directly on neurons, remains underdefined. Here, we investigate electrophysiological consequences of eCM on neuronal excitability and cell signaling mechanisms that contribute to observed phenotypes.MethodsThe split-luciferase complementation assay (LCA) was used to investigate cell signaling mechanisms downstream of tumor necrosis factor receptor 1 (TNFR1) that could contribute to changes in neuronal excitability in eCM. Whole-cell patch-clamp electrophysiology was performed in brain slices from eCM mice to elucidate consequences of infection on CA1 pyramidal neuron excitability and cell signaling mechanisms that contribute to observed phenotypes. Involvement of identified signaling molecules in mediating behavioral changes and sickness behavior observed in eCM were investigated in vivo using genetic silencing.ResultsExploring signaling mechanisms that underlie TNF-induced effects on neuronal excitability, we found that the complex assembly of fibroblast growth factor 14 (FGF14) and the voltage-gated Na+ (Nav) channel 1.6 (Nav1.6) is increased upon tumor necrosis factor receptor 1 (TNFR1) stimulation via Janus Kinase 2 (JAK2). On account of the dependency of hyperinflammatory experimental cerebral malaria (eCM) on TNF, we performed patch-clamp studies in slices from eCM mice and showed that Plasmodium chabaudi infection augments Nav1.6 channel conductance of CA1 pyramidal neurons through the TNFR1–JAK2–FGF14–Nav1.6 signaling network, which leads to hyperexcitability. Hyperexcitability of CA1 pyramidal neurons caused by infection was mitigated via an anti-TNF antibody and genetic silencing of FGF14 in CA1. Furthermore, knockdown of FGF14 in CA1 reduced sickness behavior caused by infection.ConclusionsFGF14 may represent a therapeutic target for mitigating consequences of TNF-mediated neuroinflammation.

Mononuclear cells from patients with rhupus are influenced by TNF in their production of gp130/sIL-6Rb and APRIL

ObjectiveRhupus is a rare disease that shares characteristics of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). While several studies have explored the clinical and immunological profiles of patients with...

Role of Tumor Necrosis Factor–α Inhibitors in the Treatment and Occurrence of Acne

Tumor necrosis factor-α inhibitors (TNFis) approved to treat several inflammatory diseases are sometimes used off label to treat severe forms of acne that are refractory to conventional therapies. However, use of TNFis can also be followed by acne occurrence, suggesting an association between TNFis and acne. Most of the literature on the topic comprises case reports and series that have not been reviewed in a systematic manner. To characterize the demographic characteristics, clinical presentations, treatments, and outcomes of patients receiving TNFis to treat acne and patients who develop acne following treatment of other conditions with TNFis. A systematic literature review was performed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines. PubMed and Web of Science were searched from inception through October 17, 2022. Included studies reported on patients of any sex or age who received TNFis whose treatment was followed by resolution or occurrence of acne. Two independent reviewers screened studies based on predefined criteria and extracted data from each study, which were quantitatively combined. A total of 53 studies reporting on 64 patients who received TNFis for the treatment of acne (n = 47) or who experienced acne after treatment with TNFis for a different condition (n = 17) (mean age, 28.7 years; range, 12-64 years; 6 female individuals [8.8%]) were included. The TNFis used included adalimumab, infliximab, and etanercept. Among the 47 patients treated for acne with TNFis, most had previously received antibiotics (31 [66.0%]) or isotretinoin (32 [68.1%]). Most (44 [93.6%]) experienced partial improvement (25 [53.2%]) or clearance (19 [40.4%]) with very few adverse effects reported (3 [6.4%]). Acne manifested as part of an inflammatory syndrome for 30 patients (63.8%). Among the 17 patients treated TNFis for a different condition followed by the occurrence of acne, only 1 patient (5.9%) reported having a history of acne. Therapy with TNFis was either discontinued (8 [47.1%]) or altered (6 [35.3%]) in most patients due to acne occurrence, typically with improvement in symptoms. The results of this systematic review suggest that TNFis can be effective in treating refractory acne but can also be associated with the occurrence of acne in certain instances. Further studies elucidating the role that TNF plays in treating and inducing acne could yield insight into off-label TNFi use and acne pathogenesis, potentially guiding clinical care of patients with acne treated or induced by TNFis.

TNF-α Enhances the Therapeutic Effects of MenSC-Derived Small Extracellular Vesicles on Inflammatory Bowel Disease through Macrophage Polarization by miR-24-3p.

Human menstrual blood-derived mesenchymal stem cells (MenSCs) and their secreted small extracellular vesicles (EVs) had been proven to relieve inflammation, tissue damage, and fibrosis in various organs. The microenvironment induced by inflammatory cytokines can promote mesenchymal stem cells (MSCs) to secrete more substances (including EVs) that could regulate inflammation. Inflammatory bowel disease (IBD) is a chronic idiopathic intestinal inflammation, the etiology and mechanism of which are unclear. At present, the existing therapeutic methods are ineffective for many patients and have obvious side effects. Hence, we explored the role of tumor necrosis factor α- (TNF-α-) pretreated MenSC-derived small EV (MenSCs-sEVTNF-α ) in a mouse model of dextran sulfate sodium- (DSS-) induced colitis, expecting to find better therapeutic alterations. In this research, the small EVs of MenSCs were obtained by ultracentrifugation. MicroRNAs of small EVs derived from MenSCs before and after TNF-α treatment were sequenced, and the differential microRNAs were analyzed by bioinformatics. The small EVs secreted by TNF-α-stimulating MenSCs were more effective in colonic mice than those secreted directly by MenSCs, as evidenced by the results of histopathology analysis of colonic tissue, immunohistochemistry for tight junction proteins, and enzyme-linked immunosorbent assay (ELISA) for cytokine expression profiles in vivo. The process of MenSCs-sEVTNF-α relieving colonic inflammation was accompanied by the polarization of M2 macrophages in the colon and miR-24-3p upregulation in small EVs. In vitro, both MenSC-derived sEV (MenSCs-sEV) and MenSCs-sEVTNF-α reduced the expression of proinflammatory cytokines, and MenSCs-sEVTNF-α can increase the portion of M2 macrophages. In conclusion, after TNF-α stimulation, the expression of miR-24-3p in small EVs derived from MenSCs was upregulated. MiR-24-3p was proved to target and downregulate interferon regulatory factor 1 (IRF1) expression in the murine colon and then promoted the polarization of M2 macrophages. The polarization of M2 macrophages in colonic tissues then reduced the damage caused by hyperinflammation.

Skewed fate and hematopoiesis of CD34+ HSPCs in umbilical cord blood amid the COVID-19 pandemic.

Umbilical cord blood (UCB) is an irreplaceable source for hematopoietic stem progenitor cells (HSPCs). However, the effects of SARS-CoV-2 infection and COVID-19 vaccination on UCB phenotype, specifically the HSPCs therein, are currently unknown. We thus evaluated any effects of SARS-CoV-2 infection and/or COVID-19 vaccination from the mother on the fate and functionalities of HSPCs in the UCB. The numbers and frequencies of HSPCs in the UCB decreased significantly in donors with previous SARS-CoV-2 infection and more so with COVID-19 vaccination via the induction of apoptosis, likely mediated by IFN-γ-dependent pathways. Two independent hematopoiesis assays, a colony forming unit assay and a mouse humanization assay, revealed skewed hematopoiesis of HSPCs obtained from donors delivered from mothers with SARS-CoV-2 infection history. These results indicate that SARS-CoV-2 infection and COVID-19 vaccination impair the functionalities and survivability of HSPCs in the UCB, which would make unprecedented concerns on the future of HSPC-based therapies.

Tumour necrosis factor plays a deleterious role in the pathogenesis of chikungunya virus infection.

Arthralgia is a hallmark of chikungunya virus (CHIKV) infection and can be very debilitating and associated with a robust local inflammatory response. Many pathophysiological aspects associated with the disease remain to be elucidated. Here, we describe a novel model of CHIKV infection in immunocompetent mice and evaluate the role of tumour necrosis factor in the pathogenesis of the disease. C57BL/6 wild type (WT) or TNF receptor 1 deficient (TNFR1-/- ) mice were inoculated with 1 × 106 PFU of CHIKV in the paw. Alternatively, etanercept was used to inhibit TNF in infected WT mice. Hypernociception, inflammatory and virological analysis were performed. Inoculation of CHIKV into WT mice induced persistent hypernociception. There was significant viral replication in target organs and local production of inflammatory mediators in early time-points after infection. CHIKV infection was associated with specific humoral IgM and IgG responses. In TNFR1-/- mice, there was a decrease in the hypernociception threshold, which was associated with a milder local inflammatory response in the paw but delayed viral clearance. Local or systemic treatment with etanercept reduced CHIKV-induced hypernociception. This is the first study to describe hypernociception, a clinical correlation of arthralgia, in immunocompetent mice infected with CHIKV. It also demonstrates the dual role of TNF in contributing to viral clearance but driving tissue damage and hypernociception. Inhibition of TNF may have therapeutic benefits but its role in viral clearance suggests that viral levels must be monitored in CHIKV-infected patients and that TNF inhibitors should ideally be used in combination with anti-viral drugs.

Potent anti-inflammatory activity of the lectin-like domain of TNF in joints.

In view of the crucial role of tumor necrosis factor (TNF) in joint destruction, TNF inhibitors, including neutralizing anti-TNF antibodies and soluble TNF receptor constructs, are commonly used therapeutics for the treatment of arthropathies like rheumatoid arthritis (RA). However, not all patients achieve remission; moreover, there is a risk of increased susceptibility to infection with these agents. Spatially distinct from its receptor binding sites, TNF harbors a lectin-like domain, which exerts unique functions that can be mimicked by the 17 residue solnatide peptide. This domain binds to specific oligosaccharides such as N'N'-diacetylchitobiose and directly target the α subunit of the epithelial sodium channel. Solnatide was shown to have anti-inflammatory actions in acute lung injury and glomerulonephritis models. In this study, we evaluated whether the lectin-like domain of TNF can mitigate the development of immune-mediated arthritis in mice. In an antigen-induced arthritis model, solnatide reduced cell influx and release of pro-inflammatory mediators into the joints, associated with reduction in edema and tissue damage, as compared to controls indicating that TNF has anti-inflammatory effects in an acute model of joint inflammation via its lectin-like domain.

TUMOR NECROSIS FACTOR (TNF)-α PLAYS A ROLE IN ORAL ULCERATION IN RATS

<h3>Objectives</h3> Evaluate the role of tumor necrosis factor (TNF)-α in the healing process of oral traumatic ulcers (OTUs) in rats. <h3>Study Design</h3> The animals were randomly divided into 6 experimental groups: 1 treated intravascularly with saline solution and 5 treated with infliximab at Infliximab (INF)-1, INF-INF-3, INF-5, INF-7, or INF-10 mg/kg. The animals were euthanized on days 1, 3, 7, 14, and 21 after ulceration. The ulcers were clinically measured (wound area) and the mucosa samples were histologically (scores 0-4), histomorphometrically (cell counting polymorphonuclear cells), and immunohistochemically (scores 0-3 for TNF-α and alfa-smooth muscle actin (α-SMA)) analyzed. Evans blue assay was performed to measure vascular permeability. One- and two-way analyses of variance and Kruskal-Wallis tests were performed (GraphPad Prism 5.0, <i>P</i> < .05). <h3>Results</h3> There was a reduction in the OTU area of the infliximab-treated groups (INF-5, INF-7, and INF-10) on day 1 (<i>P</i> = .043) and Evan blue extravasation (<i>P</i> = .032), polymorphonuclear cell counts (<i>P</i> = .001), and TNF-α immunostaining (<i>P</i> = .025) were significantly reduced in the dose INF-5 group compared to the saline group on the same day. In day 3, all INF-treated groups showed lower scores than the saline group (<i>P</i> = .023), but α-SMA immunostaining was reduced in day 7 in the INF-treated groups (<i>P</i> = .006). <h3>Conclusions</h3> TNF-α blockade reduced acute inflammatory process and delay wound healing in OTU.

Extracellular DNA in blood: an index of &lt;i&gt;in vivo&lt;/i&gt; inflammatory response

Increased concentration of cell-free DNA (cfDNA) in the circulating blood of humans and animals is a sign of inflammatory conditions and a distinctive characteristic of various pathophysiological processes in the body. The aim of the present study was to investigate the possible role of tumor necrosis factor (TNFα) in changes of cfDNA contents in peripheral blood as a response to experimentally induced systemic inflammation.We used 40 female hybrid mice (C57Bl/6xDBA/2) F1 at the age of 6-8 weeks. The concentration of cfDNA and its individual fractions was determined using a PicoGreen fluorescent dye. The dynamics of inflammatory process was evaluated after 4, 8, 11 and 24 hours following LPS injection. A significant increase in the blood plasma cfDNA levels was shown under the action of E. coli lipopolysaccharide (LPS), along with simultaneous decreased levels of cfDNA, associated with cell surface. The ratio of cell surface-bound cfDNA to the total cfDNA contents was reduced in dose-dependent manner as early as 4 hours after LPS injection to the animals, thus allowing us to consider this ratio a characteristic sign of netosis of neutrophilic granulocytes during the development of acute inflammation. The described effects are significantly suppressed with co-injection of recombinant TNFα neutralizing protein along with LPS, whereas increased intake of neutrophils in the tissues is determined by some other factors which are not directly related to the production of this cytokine.Based on the obtained data, we proposed a following hypothesis: induction of netosis by inflammatory stimuli causes an increase in the concentration of cfDNA in blood plasma not only due to de novo emerging extracellular DNA by neutrophil netosis, but also by the release of distinct cfDNA fraction that was previously firmly bound to cell membranes in multiple body tissues under the action of proteases released during netosis.

P346: THE ROLE OF CYTOKINES, TNF, TGFΒ1 AND NEUTROPHIL-TO-LYMPHOCYTE RATIO IN THE COURSE OF THE ACUTE LEUKEMIA

Background: Lymphocytes (Lym) and mature segmental neutrophils (Neu) together with blasts are most commonly detected in the peripheral blood (PC) of patients (pta) with acute leukemia (AL). Besides, Neu, Lym and blast cells are an important source of transforming growth factor β1 (TGFβ1), tumor necrosis factor (TNF) production. Accumulation of TNF, TGFβ1 in the plasma of AL pts is considered an unfavorable sign in AL. However, the role of TNF, TGF β1 in the relationship with neutrophil-to-lymphocyte ratio (NLR) in the course of AL is not definitively established. Aims: Determine the role of cytokines, TNF, TGF β1 in the relationship with NLR to assess the course of AL. Methods: 42 adult AL pts were examined before treatment, who at the time of the examination had blast cells in the peripheral blood (52.54 ± 5.63 x 109 / L). The NLR was calculated from peripheral blood cell counts obtained at the time of diagnosis of AL by dividing the Neu count by the Lym count. The median NLR (0.99) was used to dichotomize patients into high- NLR and low- NLR groups. The concentration of TNF, TGF β1 was determined by biological methods using sensitive cell lines L929 and CCL 64, respectively. Statistical processing of the results was estimated by the value of p ˂ 0, 005. The correlation between the indicators was estimated by the value of r. Results: There were 25 people in the low-NLR group. Median age 66 years (36 - 81 years). Among the pts were 9 people with ALL and 16 people with AML. Number of blasts 55, 83 ± 6.38 x 109 / L; New count was 11.73 ± 2.95 109 / L, Lym count - 21.27 ± 3.64 109 / L. The NLR index is 0.53 ± 0.09. In this group, 88% of pts died in the short term without achieving remission, the remaining 12% of pts had short-term remission. The concentration of TNF in plasma was 1.20 ± 0.13 ng / ml, TGF β1 - 4.02 ± 0.48 ng / ml, which in both cases was higher than in healthy individuals (p˂0.001 and p˂0.05, respectively). TNF levels were positively correlated with Lym (r = 0.30) and blasts (r = 0.40), suggesting a possible role for TNF in neoplastic clone survival. There were 17 people in the high-NLR group, including 10 pts with ALL and 7 people with AML who achieved remission. The median age is 38 years (from 16 to 68 years). The number of blasts was 33.20 ± 9.67 x 109 / L and was significantly lower than in the low-NLR group (p˂0.05); New count was 22.23 ± 0.10 x 109 / L; Lym count - 22.83 ± 3.04 109 / L. The NLR was 1.24 ± 0.16. In this group, 94% of pts had remission. Plasma TNF and TGF concentrations were lower than in the low-NLR group, apparently due to lower blast content. However, no statistical difference in cytokine concentration between the compared groups was found. Summary/Conclusion: More favorable prognostic features in AL could be NLR, the median of which is equal to or greater than 0.99. Under these conditions, a decrease in the number of blast cells, the concentration of cytokines TNF and TGF β1 in the plasma and the achievement of remission were observed. The data obtained may indicate a prognostic role of Neu and Lym blood subpopulations in the course of AL and in the relationship with cytokines, TNF and TGF β1, may be potential targets for the correction of treatment of AL pts.

The Role of Tumor Necrosis Factor Following Spinal Cord Injury: A Systematic Review.

Pre-clinical studies place tumor necrosis factor (TNF) as a central player in the inflammatory response after spinal cord injury (SCI), and blocking its production and/or activity has been proposed as a possible treatment option after SCI. This systematic review provides an overview of the literature on the temporal and cellular expression of TNF after SCI and clarifies the potential for its therapeutic manipulation in SCI. A systematic search was performed in EMBASE (Ovid), MEDLINE (Ovid), and Web of Science (Core Collection). The search terms were the MeSH forms of tumor necrosis factor and spinal cord injury in the different databases, and the last search was performed on February 3, 2021. We found twenty-four articles examining the expression of TNF, with most using a thoracic contusive SCI model in rodents. Two articles described the expression of TNF receptors in the acute phase after SCI. Twenty-one articles described the manipulation of TNF signaling using genetic knock-out, pharmaceutical inhibition, or gain-of-function approaches. Overall, TNF expression increased rapidly after SCI, within the first hours, in resident cells (neurons, astrocytes, oligodendrocytes, and microglia) and again in macrophages in the chronic phase after injury. The review underscores the complexity of TNF's role after SCI and indicates that TNF inhibition is a promising therapeutic option. This review concludes that TNF plays a significant role in the inflammatory response after SCI and suggests that targeting TNF signaling is a feasible therapeutic approach.

YAP Transcriptional Activity Dictates Cell Response to TNF In Vitro.

YAP/TAZ are transcription co-factors recently described responsive to pro-inflammatory cytokines and involved in inflammatory-related disorders. However, the role of tumor necrosis factor (TNF), a major pro-inflammatory cytokine, on YAP signaling is not well understood and controversial. Here, we observe in vitro, using wild type and YAP knockout HEK293 cells, that TNF triggers YAP nuclear translocation and transcriptional activity, thus being dependent on Rho family of GTPases. In response to TNF, YAP transcriptional activity orientates cell fate toward survival. Transcriptional analysis with Nanostring technology reveals that YAP modulates TNF-induced increase in fibro-inflammatory pathways such as NF-κB, inflammasomes, cytokines or chemokines signaling and pro-fibrotic pathways involving TGF-β and extracellular matrix remodeling. Therefore, in response to TNF, YAP acts as a sustainer of the inflammatory response and as a molecular link between inflammation and fibrotic processes. This work identifies that YAP is critical to drive several biological effects of TNF which are involved in cancer and inflammatory disorders.

Dichotomous Role of Tumor Necrosis Factor in Pulmonary Barrier Function and Alveolar Fluid Clearance.

Alveolar-capillary leak is a hallmark of the acute respiratory distress syndrome (ARDS), a potentially lethal complication of severe sepsis, trauma and pneumonia, including COVID-19. Apart from barrier dysfunction, ARDS is characterized by hyper-inflammation and impaired alveolar fluid clearance (AFC), which foster the development of pulmonary permeability edema and hamper gas exchange. Tumor Necrosis Factor (TNF) is an evolutionarily conserved pleiotropic cytokine, involved in host immune defense against pathogens and cancer. TNF exists in both membrane-bound and soluble form and its mainly -but not exclusively- pro-inflammatory and cytolytic actions are mediated by partially overlapping TNFR1 and TNFR2 binding sites situated at the interface between neighboring subunits in the homo-trimer. Whereas TNFR1 signaling can mediate hyper-inflammation and impaired barrier function and AFC in the lungs, ligand stimulation of TNFR2 can protect from ventilation-induced lung injury. Spatially distinct from the TNFR binding sites, TNF harbors within its structure a lectin-like domain that rather protects lung function in ARDS. The lectin-like domain of TNF -mimicked by the 17 residue TIP peptide- represents a physiological mediator of alveolar-capillary barrier protection. and increases AFC in both hydrostatic and permeability pulmonary edema animal models. The TIP peptide directly activates the epithelial sodium channel (ENaC) -a key mediator of fluid and blood pressure control- upon binding to its α subunit, which is also a part of the non-selective cation channel (NSC). Activity of the lectin-like domain of TNF is preserved in complexes between TNF and its soluble TNFRs and can be physiologically relevant in pneumonia. Antibody- and soluble TNFR-based therapeutic strategies show considerable success in diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease, but their chronic use can increase susceptibility to infection. Since the lectin-like domain of TNF does not interfere with TNF’s anti-bacterial actions, while exerting protective actions in the alveolar-capillary compartments, it is currently evaluated in clinical trials in ARDS and COVID-19. A more comprehensive knowledge of the precise role of the TNFR binding sites versus the lectin-like domain of TNF in lung injury, tissue hypoxia, repair and remodeling may foster the development of novel therapeutics for ARDS.

The Role of Tumor Necrosis Factor Associated Factors (TRAFs) in Vascular Inflammation and Atherosclerosis.

TNF receptor associated factors (TRAFs) represent a family of cytoplasmic signaling adaptor proteins that regulate, bundle, and transduce inflammatory signals downstream of TNF- (TNF-Rs), interleukin (IL)-1-, Toll-like- (TLRs), and IL-17 receptors. TRAFs play a pivotal role in regulating cell survival and immune cell function and are fundamental regulators of acute and chronic inflammation. Lately, the inhibition of inflammation by anti-cytokine therapy has emerged as novel treatment strategy in patients with atherosclerosis. Likewise, growing evidence from preclinical experiments proposes TRAFs as potent modulators of inflammation in atherosclerosis and vascular inflammation. Yet, TRAFs show a highly complex interplay between different TRAF-family members with partially opposing and overlapping functions that are determined by the level of cellular expression, concomitant signaling events, and the context of the disease. Therefore, inhibition of specific TRAFs may be beneficial in one condition and harmful in others. Here, we carefully discuss the cellular expression and signaling events of TRAFs and evaluate their role in vascular inflammation and atherosclerosis. We also highlight metabolic effects of TRAFs and discuss the development of TRAF-based therapeutics in the future.

The possible protective role of N-acetyl cysteine on duodenal mucosa of high fat diet and orlistat treated adult male albino rats and the active role of tumor necrosis factor α (TNFα) and Interleukin 6 (IL6) (histological and biochemical study)

ABSTRACT Background Obesity is a major universal health issue linked to a majority of illness. Aim To evaluate the histological and biochemical changes occurred in the duodenal mucosa of high fat diet HFD and orlistat fed rats and to assess the possible protective role of N-acetyl cysteine NAC supplementation. Material and method Sixty male albino rats weighing 180–200 g were classified randomly into control group I and three experimental groups (HFD group II, HFD + orlistat group III, and HFD + orlistat + NAC group IV). All experimental groups received HFD alone/and treatment for 6 weeks. Group III received orlistat (32 mg/kg/day) before meals and group IV received the same regimen as group III in addition to NAC (230 mg/kg/day) after meals. After completion of the experiment, duodenal sections were processed for histological examination, oxidative stress parameters, and semiqualitative real time PCR for proinflammatory mediators TNFα and IL6 evaluation. Also, plasma lipid parameters were assessed and morphometric duodenal results were analyzed statistically. Results By histological examination of HFD and (HFD + orlistat) groups, we found severe to moderate duodenal structural disturbances, increased goblet cells, collagen fibers, and BAX and iNOS immunostaining. By Biochemical examination, both groups showed increased proinflammatory markers level (TNFα and IL6) with decreased all antioxidant parameters and increased MDA. Moreover, NAC treatment in group IV significantly reduced all structural changes, levels of proinflammatory mediators and increased all antioxidant parameter levels and decreased MDA. Conclusion All findings elucidated that NAC could be accounted to be a useful drug for protection of duodenal mucosa of HFD and orlistat treated animals.

Показники центральної гемодинаміки у хворих на цукровий діабет 2-го типу з неалкогольною жировою хворобою печінки. Взаємозв’язок з фактором некрозу пухлини α та інтерлейкіном-6

У роботі вивчені показники центральної гемодинаміки у пацієнтів із цукровим діабетом 2-го типу в поєднанні з неалкогольною жировою хворобою печінки. Виявлено клінічно значуще підвищення показників запалення низької інтенсивності (фактор некрозу пухлини α, інтерлейкін-6), а також встановлено їх негативний кореляційний зв’язок із структурно-функціональними показниками лівого шлуночка, що свідчить про негативну роль фактора некрозу пухлини α та інтерлейкіну-6 в ремоделюванні міокарда.