TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants – past, present and future
TL;DR: The therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.
About: This article is published in Cytokine & Growth Factor Reviews.The article was published on 2014-08-01 and is currently open access. It has received 645 citations till now. The article focuses on the topics: Adalimumab & Etanercept.
Citations
More filters
TL;DR: This review has focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies and novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.
Abstract: As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.
398 citations
Cites background from "TNF and TNF-receptors: From mediato..."
...Caspase-8 then activates caspase-3 responsible for apoptotic cell death [120]....
[...]
...cell death occurs only under stress conditions such as altered cell metabolism, inhibition of cell cycle progression, and protein synthesis [120]....
[...]
TL;DR: The epidemiological evidence for the cardiovascular effects of PM exposure is reviewed and current understanding about the biological mechanisms, by which PM exerts toxic effects on cardiovascular system to induce cardiovascular disease are discussed.
Abstract: Air pollution is a complex mixture of gaseous and particulate components, each of which has detrimental effects on human health. While the composition of air pollution varies greatly depending on the source, studies from across the world have consistently shown that air pollution is an important modifiable risk factor for significantly increased morbidity and mortality. Moreover, clinical studies have generally shown a greater impact of particulate matter (PM) air pollution on health than the gaseous components. PM has wide-ranging deleterious effects on human health, particularly on the cardiovascular system. Both acute and chronic exposure to PM air pollution is associated with increased risk of death from cardiovascular diseases including ischemic heart disease, heart failure, and ischemic/thrombotic stroke. Particulate matter has also been shown to be an important endocrine disrupter, contributing to the development of metabolic diseases such as obesity and diabetes mellitus, which themselves are risk factors for cardiovascular disease. While the epidemiological evidence for the deleterious effects of PM air pollution on health is increasingly accepted, newer studies are shedding light on the mechanisms by which PM exerts its toxic effects. A greater understanding of how PM exerts toxic effects on human health is required in order to prevent and minimize the deleterious health effects of this ubiquitous environmental hazard. Air pollution is a growing public health problem and mortality due to air pollution is expected to double by 2050. Here, we review the epidemiological evidence for the cardiovascular effects of PM exposure and discuss current understanding about the biological mechanisms, by which PM exerts toxic effects on cardiovascular system to induce cardiovascular disease.
325 citations
Cites background from "TNF and TNF-receptors: From mediato..."
...TNFα has since been shown to be a critical regulator of the cytokine cascade in many inflammatory diseases and is a therapeutic target for a number of chronic inflammatory diseases (179, 180)....
[...]
TL;DR: The molecular mechanisms of necroptosis and its relevance to diseases are discussed, with a focus on cancer, neurodegenerative diseases, and inflammatory diseases.
Abstract: Programmed cell death has a vital role in embryonic development and tissue homeostasis. Necroptosis is an alternative mode of regulated cell death mimicking features of apoptosis and necrosis. Necroptosis requires protein RIPK3 (previously well recognized as regulator of inflammation, cell survival, and disease) and its substrate MLKL, the crucial players of this pathway. Necroptosis is induced by toll-like receptor, death receptor, interferon, and some other mediators. Shreds of evidence based on a mouse model reveals that deregulation of necroptosis has been found to be associated with pathological conditions like cancer, neurodegenerative diseases, and inflammatory diseases. In this timeline article, we are discussing the molecular mechanisms of necroptosis and its relevance to diseases.
325 citations
Cites background from "TNF and TNF-receptors: From mediato..."
...iasis, bowel disease, and rheumatoid arthritis [19, 20] and regulates production of chemokines and cytokines as primary outcomes of TNF stimulation [21]....
[...]
TL;DR: An ideal therapeutic strategy for autoimmune diseases would be to selectively block the sTNF/TNFR1 signal through the administration of sT NF inhibitors, or using TNFR1 antagonists while keeping the TNFR2 signaling pathway intact.
Abstract: Tumor Necrosis Factor α (TNFα) is a pleiotropic cytokine which signals through TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Emerging evidence has demonstrated that TNFR1 is ubiquitously expressed on almost all cells, while TNFR2 exhibits a limited expression, predominantly on regulatory T cells (Tregs). Additionally, the signaling pathway by sTNF via TNFR1 mainly triggers pro-inflammatory pathways, and mTNF binding to TNFR2 usually initiates immune modulation and tissue regeneration. TNFα plays a critical role in up-regulation or down-regulation of Treg activity. Deficiency in TNFR2 signaling is significant in various autoimmune diseases. An ideal therapeutic strategy for autoimmune diseases would be to selectively block the sTNF/TNFR1 signal through the administration of sTNF inhibitors, or using TNFR1 antagonists while keeping the TNFR2 signaling pathway intact. Another promising strategy would be to rely on TNFR2 agonists which could drive the expansion of Tregs and promote tissue regeneration. Design of these therapeutic strategies targeting the TNFR1 or TNFR2 signaling pathways holds promise for the treatment of diverse inflammatory and degenerative diseases.
239 citations
TL;DR: This Review discusses the key considerations and potential pitfalls of immune agonist antibody design and development, their differentiating features from antagonist antibodies and the landscape of agonist antibodies in clinical development for cancer treatment.
Abstract: Immune cell functions are regulated by co-inhibitory and co-stimulatory receptors. The first two generations of cancer immunotherapy agents consist primarily of antagonist antibodies that block negative immune checkpoints, such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte protein 4 (CTLA4). Looking ahead, there is substantial promise in targeting co-stimulatory receptors with agonist antibodies, and a growing number of these agents are making their way through various stages of development. This Review discusses the key considerations and potential pitfalls of immune agonist antibody design and development, their differentiating features from antagonist antibodies and the landscape of agonist antibodies in clinical development for cancer treatment.
234 citations
References
More filters
TL;DR: It is proposed that TNF mediates endotoxin-induced tumor necrosis, and that it may be responsible for the suppression of transformed cells by activated macrophages.
Abstract: In studying "hemorrhagic necrosis" of tumors produced by endotoxin, it was found that the serum of bacillus Calmette--Guerin (BCG)-infected mice treated with endotoxin contains a substance (tumor necrosis factor; TNF) which mimics the tumor necrotic action of endotoxin itself. TNF-positive serum is as effective as endotoxin itself in causing necrosis of the sarcoma Meth A and other transplanted tumors. A variety of tests indicate that TNF is not residual endotoxin, but a factor released from host cells, probably macrophages, by endotoxin. Corynebacteria and Zymosan, which like BCG induce hyperplasia of the reticulo-endothelial system, can substitute for BCG in priming mice for release of TNF by endotoxin. TNF is toxic in vitro for two neoplastic cell lines; it is not toxic for mouse embryo cultures. We propose that TNF mediates endotoxin-induced tumor necrosis, and that it may be responsible for the suppression of transformed cells by activated macrophages.
4,490 citations
"TNF and TNF-receptors: From mediato..." refers background in this paper
...TNF was discovered in 1975 as an endotoxin-inducible molecule that caused necrosis of tumors in vitro [1]....
[...]
...LPS (endotoxin) – a biological inducer of TNF [1]....
[...]
TL;DR: Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.
Abstract: Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of...
4,275 citations
"TNF and TNF-receptors: From mediato..." refers background in this paper
...However, it is pharmacologically well characterized and considered safe even at high concentrations [186,187]....
[...]
TL;DR: A caspase-activated deoxyribonuclease (CAD) and its inhibitor (ICAD) have now been identified in the cytoplasmic fraction of mouse lymphoma cells and seems to function as a chaperone for CAD during its synthesis, remaining complexed with CAD to inhibit its DNase activity.
Abstract: The homeostasis of animals is regulated not only by the growth and differentiation of cells, but also by cell death through a process known as apoptosis. Apoptosis is mediated by members of the caspase family of proteases, and eventually causes the degradation of chromosomal DNA. A caspase-activated deoxyribonuclease (CAD) and its inhibitor (ICAD) have now been identified in the cytoplasmic fraction of mouse lymphoma cells. CAD is a protein of 343 amino acids which carries a nuclear-localization signal; ICAD exists in a long and a short form. Recombinant ICAD specifically inhibits CAD-induced degradation of nuclear DNA and its DNase activity. When CAD is expressed with ICAD in COS cells or in a cell-free system, CAD is produced as a complex with ICAD: treatment with caspase 3 releases the DNase activity which causes DNA fragmentation in nuclei. ICAD therefore seems to function as a chaperone for CAD during its synthesis, remaining complexed with CAD to inhibit its DNase activity; caspases activated by apoptotic stimuli then cleave ICAD, allowing CAD to enter the nucleus and degrade chromosomal DNA.
3,248 citations
"TNF and TNF-receptors: From mediato..." refers background in this paper
...The activation of caspase-3, in particular, is essential for TNF-induced cell death, as it targets a latent DNAse that degrades genomic DNA [60] thus causing apoptotic cell death; the caspase activated DNase (CAD) [60]....
[...]
...Before long, these proteins were purified and characterized, the murine and human cDNAs were cloned [12–14], and thus began the exciting era of anti-TNF cytokine therapy....
[...]
...Upon the phosphorylation and ubiquitindependent degradation of IKK, NF-kB transcription factors translocate into the nucleus where they bind to DNA and function as transcriptional activators....
[...]
...degrades genomic DNA [60] thus causing apoptotic cell death; the caspase activated DNase (CAD) [60]....
[...]
TL;DR: This work utilized nano-electrospray tandem mass spectrometry to identify CAP3 and CAP4, components of the CD95 (Fas/APO-1) death-inducing signaling complex, and found a novel 55 kDa protein, designated FLICE, which has homology to both FADD and the ICE/CED-3 family of cysteine proteases.
3,181 citations
"TNF and TNF-receptors: From mediato..." refers background in this paper
...but contains a death-effector domain (DED) that permits its interactions with pro-caspase-8 as well as other DED containing proteins [61], thus preventing constitutive pro-caspase-8 recruitment to the TNFR1 DISC....
[...]
TL;DR: The results should facilitate the development of therapeutically useful inhibitors of TNF-α release, and they indicate that an important function of adamalysins may be to shed cell-surface proteins.
Abstract: Mammalian cells proteolytically release (shed) the extracellular domains of many cell-surface proteins. Modification of the cell surface in this way can alter the cell's responsiveness to its environment and release potent soluble regulatory factors. The release of soluble tumour-necrosis factor-alpha (TNF-alpha) from its membrane-bound precursor is one of the most intensively studied shedding events because this inflammatory cytokine is so physiologically important. The inhibition of TNF-alpha release (and many other shedding phenomena) by hydroxamic acid-based inhibitors indicates that one or more metalloproteinases is involved. We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. Inactivation of the gene in mouse cells caused a marked decrease in soluble TNF-alpha production. This enzyme (called the TNF-alpha-converting enzyme, or TACE) is a new member of the family of mammalian adamalysins (or ADAMs), for which no physiological catalytic function has previously been identified. Our results should facilitate the development of therapeutically useful inhibitors of TNF-alpha release, and they indicate that an important function of adamalysins may be to shed cell-surface proteins.
3,007 citations
"TNF and TNF-receptors: From mediato..." refers background in this paper
...As a transmembrane protein expressed on the surface of cells, membrane TNF (also sometimes referred to as pro-TNF) is cleaved by a metalloprotease, TNFa-converting enzyme (TACE) [32,33]....
[...]