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Tumor Necrosis Factor (TNF) II

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 30553

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Prof. Dr. Daniela Basso

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Laboratory Medicine, Department of Medicine—DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
Interests: pancreatic neoplasms; H.pylori; inflammatory bowel diseases; celiac disease; biomarkers; cytokines; laboratory medicine
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Dear Colleagues,

Tumor Necrosis Factor (TNF) and its receptors TNFR1 and TNFR2 are the best-characterized members of the TNFSF and TNFRSF superfamilies, which include, to date, 19 ligands and 29 receptors. TNFSF members have in common the ability to promote pro-inflammatory signals, but they might regulate other cellular functions, such as cell-to-cell communication, differentiation, survival, apoptosis, and necroptosis. TNF activates several intracellular signaling pathways, including NF-kB, JNK, apoptosis (caspase 8 activation), and necroptosis (phosphorylation of RIPK1, RIPK3, and MLKL), of which constant balance regulates the opposite cell fates proliferation and death.

TNF, which is mainly produced by macrophages, NK, and Th1 T lymphocytes, plays a central role in innate and adaptive immunity and in chronic inflammatory diseases, such as those of the joints, including rheumatoid arthritis and spondiloarthris, and those of the intestine, namely the inflammatory bowel diseases. Chronic inflammation, including the TNF–TNFR pathway’s activation, is increasingly being recognized as involved in cancer, obesity, diabetes, cardiovascular diseases, and neurodegenerative disorders. Five drugs blocking TNF–TNFR signaling have been approved for the therapy of chronic inflammatory rheumatic and intestinal diseases. However, the number of these drugs and the number of individuals with diseases that might benefit from this type of treatment, are expected to increase greatly in the near future. This Special Issue on “Tumor Necrosis Factor (TNF)” aims to address the biology of the TNF–TNFR pathway and present the newest knowledge on its role in diseases characterized by chronic inflammation and on established and emerging therapies that target TNF signaling.

Prof. Dr. Daniela Basso
Guest Editor

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Keywords

Tumor Necrosis Factor (TNF);
TNF receptors;
Inflammation;
Signaling;
Arthritis;
Cancer;
Metabolic syndrome;
Anti-TNF agents.

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Published Papers (7 papers)

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19 pages, 2802 KiB

Open AccessArticle

Defective Regulation of Membrane TNFα Expression in Dendritic Cells of Glioblastoma Patients Leads to the Impairment of Cytotoxic Activity against Autologous Tumor Cells

by Tamara Tyrinova, Olga Leplina, Sergey Mishinov, Marina Tikhonova, Evgeniya Dolgova, Anastasiya Proskurina, Vyacheslav Stupack, Sergey Bogachev, Alexander Ostanin and Elena Chernykh

Int. J. Mol. Sci. 2020, 21(8), 2898; https://doi.org/10.3390/ijms21082898 - 21 Apr 2020

Cited by 5 | Viewed by 2492

Abstract

Besides an antigen-presenting function and ability to induce antitumor immune responses, dendritic cells (DCs) possess a direct tumoricidal activity. We previously reported that monocyte-derived IFNα-induced DCs (IFN-DCs) of glioblastoma multiforme patients express low levels of membrane TNFα molecule (mTNFα) and have impaired TNFα/TNF-R1-mediated cytotoxicity against immortalized tumor cell line HEp-2. However, whether the observed defect could affect killer activity of glioma patient DCs against autologous tumor cells remained unclear. Here, we show that donor IFN-DCs possess cytotoxic activity against glioblastoma cell lines derived from a primary tumor culture. Granule-mediated and TNFα/TNF-R1-dependent pathways were established as the main mechanisms underlying cytotoxic activity of IFN-DCs. Glioblastoma patient IFN-DCs showed lower cytotoxicity against autologous glioblastoma cells sensitive to TNFα/TNFR1-mediated lysis, which was associated with low TNFα mRNA expression and high TACE/ADAM-17 enzyme activity. Recombinant IL-2 (rIL-2) and human double-stranded DNA (dsDNA) increased 1.5-fold cytotoxic activity of patient IFN-DCs against autologous glioblastoma cells. dsDNA, but not rIL-2, enhanced the expression of TNFα mRNA and decreased expression and activity of TACE/ADAM-17 enzyme. In addition, dsDNA and rIL-2 stimulated the expression of perforin and granzyme B (in the presence of dsDNA), suggesting the possibility of enhancing DC cytotoxicity against autologous glioblastoma cells via various mechanisms. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) II)

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15 pages, 4240 KiB

Open AccessArticle

New Insights on the Effect of TNF Alpha Blockade by Gene Silencing in Noise-Induced Hearing Loss

by Janaína C. Rodrigues, André L. L. Bachi, Gleiciele A. V. Silva, Marcelo Rossi, Jonatas B. do Amaral, Karina Lezirovitz and Rubens de Brito

Int. J. Mol. Sci. 2020, 21(8), 2692; https://doi.org/10.3390/ijms21082692 - 13 Apr 2020

Cited by 8 | Viewed by 2594

Abstract

Noise exposure represents the second most common cause of acquired sensorineural hearing loss and we observed that tumor necrosis factor α (TNFα) was involved in this context. The effect of Tnfα gene silencing on the expression profile related to the TNFα metabolic pathway in an experimental model of noise-induced hearing loss had not previously been studied. Methods: Single ears of Wistar rats were pretreated with Tnfα small interfering RNA (siRNA) by trans-tympanic administration 24 h before they were exposed to white noise (120 dBSPL for three hours). After 24 h of noise exposure, we analyzed the electrophysiological threshold and the amplitude of waves I, II, III, and IV in the auditory brain response click. In addition, qRT-PCR was performed to evaluate the TNFα metabolic pathway in the ears submitted or not to gene silencing. Results: Preservation of the electrophysiological threshold and the amplitude of waves was observed in the ears submitted to gene silencing compared to the ears not treated. Increased anti-apoptotic gene expression and decreased pro-apoptotic gene expression were found in the treated ears. Conclusion: Our results allow us to suggest that the blockade of TNFα by gene silencing was useful to prevent noise-induced hearing loss. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) II)

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13 pages, 971 KiB

Open AccessArticle

Co-Expression Profile of TNF Membrane-Bound Receptors Type 1 and 2 in Rheumatoid Arthritis on Immunocompetent Cells Subsets

by Alina Alshevskaya, Julia Lopatnikova, Julia Zhukova, Oksana Chumasova, Nadezhda Shkaruba, Aleksey Sizikov, Irina Evsegneeva, Victor Gladkikh, Aleksander Karaulov and Sergey V. Sennikov

Int. J. Mol. Sci. 2020, 21(1), 288; https://doi.org/10.3390/ijms21010288 - 31 Dec 2019

Cited by 8 | Viewed by 2395

Abstract

Introduction: Tumor necrosis factor (TNFα) is an important proinflammatory cytokine in rheumatoid arthritis (RA) immune processes. However, TNFα activity and functions may be regulated by soluble receptors, which act as decoys, and by number, density, and co-expression of its membrane-bound receptors type 1 and 2 (TNFR1 and TNFR2). The aim of this study was to reveal associations between TNFR1/2 co-expression profile parameters and RA disease activity indicators. Methods: PBMC were analyzed from 46 healthy donors and 64 patients with RA using flow cytometry. Patients were divided according to the disease activity score (DAS) 28 index into groups with high (n = 22, 34.4%), moderate (n = 30, 46.9%), and low (n = 12, 18.8%) disease activity. Co-expression of TNFR1 and TNFR2 was studied by evaluating the percentage of cells, with different receptors, and by counting the number of receptors of each type per cell, using QuantiBritePE beads. Associations between disease severity and activity indicators and parameters of TNFα receptor expression in subpopulations of immune cells were studied. Results: T cell subsets from RA patients were characterized by co-expression of TNFR1 and TNFR2, and were found to differ significantly compared with healthy donors. Memory cells both among T helper cells and cytotoxic T cells demonstrated the most significant differences in TNFR-expression profile. Multivariable logistic regression revealed model to identified RA patients from healthy individual based on the TNFR1/2 co-expression parameters. Conclusion: The profile of TNFR1\2 co-expression differs in RA comparing with health. Proportion of TNFR1+TNFR2- cells increased significantly among memory T helper cells and activated cytotoxic T cells, and decreased significantly among naïve cytotoxic T cells and T regulatory cells as compared with health. The parameters of TNFR1\2 co-expression in RA are associated with clinical and laboratory indicators of disease activity. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) II)

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22 pages, 2207 KiB

Open AccessArticle

Mechanism of Action of the Tumor Vessel Targeting Agent NGR-hTNF: Role of Both NGR Peptide and hTNF in Cell Binding and Signaling

by Barbara Valentinis, Simona Porcellini, Claudia Asperti, Manuela Cota, Dan Zhou, Paola Di Matteo, Gianpiero Garau, Chiara Zucchelli, Nilla Roberta Avanzi, Gian Paolo Rizzardi, Massimo Degano, Giovanna Musco and Catia Traversari

Int. J. Mol. Sci. 2019, 20(18), 4511; https://doi.org/10.3390/ijms20184511 - 12 Sep 2019

Cited by 14 | Viewed by 3847

Abstract

NGR-hTNF is a therapeutic agent for a solid tumor that specifically targets angiogenic tumor blood vessels, through the NGR motif. Its activity has been assessed in several clinical studies encompassing tumors of different histological types. The drug’s activity is based on an improved permeabilization of newly formed tumor vasculature, which favors intratumor penetration of chemotherapeutic agents and leukocyte trafficking. This work investigated the binding and the signaling properties of the NGR-hTNF, to elucidate its mechanism of action. The crystal structure of NGR-hTNF and modeling of its interaction with TNFR suggested that the NGR region is available for binding to a specific receptor. Using 2D TR-NOESY experiments, this study confirmed that the NGR-peptides binds to a specific CD13 isoform, whose expression is restricted to tumor vasculature cells, and to some tumor cell lines. The interaction between hTNF or NGR-hTNF with immobilized TNFRs showed similar kinetic parameters, whereas the competition experiments performed on the cells expressing both TNFR and CD13 showed that NGR-hTNF had a higher binding affinity than hTNF. The analysis of the NGR-hTNF-triggered signal transduction events showed a specific impairment in the activation of pro-survival pathways (Ras, Erk and Akt), compared to hTNF. Since a signaling pattern identical to NGR-hTNF was obtained with hTNF and NGR-sequence given as distinct molecules, the inhibition observed on the survival pathways was presumably due to a direct effect of the NGR-CD13 engagement on the TNFR signaling pathway. The reduced activation of the pro survival pathways induced by NGR-hTNF correlated with the increased caspases activation and reduced cell survival. This study demonstrates that the binding of the NGR-motif to CD13 determines not only the homing of NGR-hTNF to tumor vessels, but also the increase in its antiangiogenic activity. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) II)

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Review

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18 pages, 1575 KiB

Open AccessReview

Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives

by Cornelia Cudrici, Natalie Deuitch and Ivona Aksentijevich

Int. J. Mol. Sci. 2020, 21(9), 3263; https://doi.org/10.3390/ijms21093263 - 5 May 2020

Cited by 63 | Viewed by 10653

Abstract

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory syndrome characterized by prolonged and recurrent episodes of fever, abdominal and/or chest pain, arthralgia, myalgia, and erythematous rash. TRAPS is associated with heterozygous variants in the TNFRSF1A gene, which encodes the TNFR1 (tumor necrosis factor receptor 1) receptor. Disease-causing variants are found exclusively in the extracellular domain of TNFR1 and affect receptor structure and binding to the TNF ligand. The precise mechanism of the disease is still unclear, but it is thought that intracellular accumulation of misfolded mutant protein leads to endoplasmic reticulum stress and enhanced inflammatory responses through constitutive activation of various immune pathways. Other possible mechanisms contributing to the disease pathogenesis include defective receptor shedding, TNF-induced cell death, production of reactive oxygen species, and autophagy impairment. Patients’ leucocytes are hyperresponsive to stimulation and produce elevated levels of proinflammatory cytokines. Systemic autoimmune (AA) amyloidosis is an important cause of morbidity and mortality in TRAPS. Over the last two decades, new therapies have changed the progression and outcome of the disease. In this review, we summarize clinical data from 209 patients with validated pathogenic variants reported in the literature and discuss TRAPS diagnosis, pathogenesis, and treatment options. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) II)

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14 pages, 448 KiB

Open AccessReview

Behҫet’s Disease, and the Role of TNF-α and TNF-α Blockers

by Tim van der Houwen and Jan van Laar

Int. J. Mol. Sci. 2020, 21(9), 3072; https://doi.org/10.3390/ijms21093072 - 27 Apr 2020

Cited by 21 | Viewed by 3166

Abstract

In this both narrative and systematic review, we explore the role of TNF-α in the immunopathogenesis of Behçet’s disease (BD) and the effect of treatment with TNF-α blockers. BD is an auto-inflammatory disease, characterized by recurrent painful oral ulcerations. The pathogenesis of BD is not yet elucidated; it is assumed that TNF-α may play a key role. In the narrative review, we report an increased production of TNF-α, which may be stimulated via TLR-signaling, or triggered by increased levels of IL-1β and IFN-γ. The abundance of TNF-α is found in both serum and in sites of inflammation. This increased presence of TNF-α stimulates T-cell development toward pro-inflammatory subsets, such as Th17 and Th22 cells. Treatment directed against the surplus of TNF-α is investigated in the systematic review, performed according to the PRISMA guideline. We searched the Pubmed and Cochrane database, including comparative studies only. After including 11 studies, we report a beneficial effect of treatment with TNF-α blockers on the various manifestations of BD. In conclusion, the pivotal role of TNF-α in the immunopathogenesis of BD is reflected in both the evidence of their pro-inflammatory effects in BD and in the evidence of the positive effect of treatment on the course of disease in BD. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) II)

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19 pages, 623 KiB

Open AccessReview

Different Original and Biosimilar TNF Inhibitors Similarly Reduce Joint Destruction in Rheumatoid Arthritis—A Network Meta-Analysis of 36 Randomized Controlled Trials

by Niels Graudal, Benjamin Skov Kaas-Hansen, Louise Guski, Thorbjørn Hubeck-Graudal, Nicky J. Welton and Gesche Jürgens

Int. J. Mol. Sci. 2019, 20(18), 4350; https://doi.org/10.3390/ijms20184350 - 5 Sep 2019

Cited by 18 | Viewed by 4772

Abstract

The effect of five approved tumour necrosis factor inhibitors (TNFi: infliximab, etanercept, adalimumab, certolizumab, and golimumab) on joint destruction in rheumatoid arthritis (RA) have been compared versus methotrexate (MTX) in randomized controlled trials (RCTs) but have not been compared directly to each other or to an otherwise untreated placebo control. The present analysis compares effects of standard doses, high doses, and low doses of TNFis on radiographic joint destruction in RA and relate these effects to MTX and placebo by means of a Bayesian network meta-analysis. We identified 31 RCTs of the effect of TNFis on joint destruction and 5 RCTs with controls, which indirectly could link otherwise untreated placebo controls to the TNFi treatments in the network. The previously untested comparison with placebo was performed to estimate not only the effect relative to another drug, but also the absolute attainable effect. Compared to placebo there was a highly significant inhibitory effect on joint destruction of infliximab, etanercept, adalimumab, certolizumab, and golimumab, which was about 0.9% per year as monotherapy and about 1.2% per year when combined with MTX. Although significantly better than MTX and placebo, golimumab seemed inferior to the remaining TNFis. There was no difference between original reference drugs (Remicade, Enbrel) and the almost identical copy drugs (biosimilars). Full article

(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) II)

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