Tumor necrosis factor (TNF), also known as cachexin or cachectin, is a cytokine and a member of the TNF superfamily, which comprises various transmembrane proteins with a homologous TNF domain. Initially referred to as TNFα (with or without a dash), this cytokine was the first to be identified as an adipokine, secreted by adipose tissue. TNF signaling occurs through two receptors: TNFR1 and TNFR2.[1] [2] TNFR1 is widely expressed across most cell types and is typically associated with pro-inflammatory and apoptotic signaling. In contrast, TNFR2 is mainly found on endothelial, epithelial, and immune cells, where it mediates anti-inflammatory responses and promotes cell proliferation.[3]
TNF-α exists in both transmembrane (mTNF-α) and soluble forms (sTNF-α). The soluble form is generated through enzymatic cleavage of the transmembrane form, a process known as substrate presentation.[4] The transmembrane form predominantly interacts with both TNFR1 and TNFR2 through cell-to-cell contact, whereas the soluble form primarily binds to TNFR1.[5] Binding of TNF-α to TNFR1 is irreversible, leading to prolonged signaling, whereas its binding to TNFR2 is reversible.[6]
The primary role of TNF is to regulate immune cells. As an endogenous pyrogen, TNF can induce fever, trigger apoptosis, cause cachexia, and initiate inflammation. It plays a critical role in inhibiting tumorigenesis and viral replication and in responding to sepsis in conjunction with IL-1 and IL-6. However, dysregulated TNF production is linked to several diseases, including Alzheimer's disease,[7] cancer,[8] major depression,[9] psoriasis,[10] and inflammatory bowel disease (IBD).[11]
As an adipokine, TNF contributes to insulin resistance and is strongly associated with obesity-induced type 2 diabetes.[12] As a cytokine, TNF plays a crucial role in the immune system by serving as a key mediator in cell signaling. When macrophages detect an infection, they release TNF to alert other immune cells, initiating an inflammatory response. Certain cancers can lead to overproduction of TNF, which, similar to parathyroid hormone, can cause secondary hypercalcemia. Under the name tasonermin, TNF is used as an immunostimulant drug in the treatment of certain cancers. Conversely, drugs that inhibit TNF are used to treat various inflammatory diseases, such as rheumatoid arthritis.
In the 1890s, William B. Coley, based on anecdotes of cancer patients being cured by sudden attacks of erysipelas, theorized that bacterial infections had a beneficial effect against tumors, particularly sarcomas. Coley was able to successfully treat cancer patients by injecting them with a mixture of bacterial toxins from heat-sterilized Streptococcus and Bacillus prodigiosus in and around the tumors, causing the tumors to hemorrhage. However, the effectiveness of this treatment was inconsistent and repeated injections caused severe side effects such as chills and fevers, causing the treatment to be discontinued.[13]
In the 1930s and 1940s, Shear et al. isolated the active tumor-hemorrhaging agent from the bacterial toxins of Escherichia coli and Serratia marcescens. They demonstrated that this agent, endotoxin, when injected into mice with sarcomas, could inhibit tumor growth or cause tumor regression.[14] However, tumor regression was highly variable, with smaller doses of endotoxin often having more potency than larger doses, or entire batches of mice being resistant to the endotoxin.[15]
In 1975, Elizabeth Carswell and Lloyd Old et al. investigated the tumor-killing properties of endotoxin by extracting serum from donor mice injected with endotoxin, and injecting the serum into recipient mice carrying transplanted sarcomas. They discovered that donor mice infected with Bacillus Calmette Guerin (BCG), upon exposure to endotoxin, produced serum that caused the tumors to hemorrhage in the recipient mice. The serum of BCG-infected donor mice did not contain residual endotoxins, leading the authors to conclude that the serum contained a separate cytotoxic factor, termed Tumor Necrosis Factor (TNF). Since BCG-infected mice had enlarged spleens due to an increased production of macrophages, the authors deduced that TNF was released by macrophages upon exposure to endotoxins.[16]
In addition to causing sarcomas to hemorrhage in vivo, TNF was also cytotoxic to L-929 cells, a transformed cell line, in vitro. Cytotoxicity to L-929 cells in vitro became the standard technique for detecting TNF. [17] TNF was cytotoxic to cancerous and transformed cell lines, but not to normal, untransformed cell lines, raising hopes that it could be used as a cancer therapy. [16]
In August 1984, Bharat Aggarwal et al. at Genentech purified and characterized human TNF. The TNF was produced by culturing HL-60, a human cell line, with phorbol myristate acetate (PMA), a phagocyte stimulant similar to endotoxin. The TNF was purified using controlled pore glass beads, DEAE chromatography, Mono Q chromatography, and reversed-phase HPLC. TNF purified using reversed-phase HPLC was determined to have a molecular weight of 17,000 kDa by SDS-PAGE, whereas TNF purified using TSK-HPLC under nondenaturing conditions was determined to have an approximate molecular weight of 45,000 kDa, suggesting that TNF naturally exists as an oligomer. The TNF amino acid sequence was determined using Edman degradation, revealing a sequence of 157 amino acids with significant homology to the amino acid sequence of lymphotoxin. [18]
In that same month, Pennica et al, also at Genentech, sequenced the cDNA of human TNF. A cDNA library was constructed from the mRNA of HL-60 cells induced by PMA. A 42-base long DNA probe, constructed by guessing the codons of a portion of the TNF amino acid sequence, was used to screen the cDNA library. The matching cDNA was sequenced, revealing a presequence of 76 amino acids followed by the 157 amino acids of mature TNF. The authors deduced that TNF is first synthesized into a larger precursor form containing a signal peptide, before being processed and released as a smaller mature form. The authors also synthesized TNF in e coli and verified its cytotoxicity against L-929 cells in vitro and against mouse sarcomas in vivo. [19]
In June 1981, Ian A. Clark et al. found that healthy mice infected with Plasmodium vinckei, a malaria-causing parasite, upon exposure to endotoxin, developed malaria-like symptoms such as liver damage, hypoglycemia, and blood clotting, while also releasing mediators including TNF. Uninfected mice did not release these mediators when injected with endotoxin. These results, combined with evidence of endotoxins in the serum of malaria patients, led the authors to propose that mediators such as TNF are present in acute malaria infections, and that they play a role in causing malaria symptoms. [20]
In 1985, Kevin J. Tracy, Ian Milsark, and Anthony Cerami found that mice immunized from TNF via TNF antiserum were resistant to the lethal effects of endotoxin, indicating that TNF is one of the mediators of endotoxin lethality. [21] In 1986, this was confirmed by Kevin J. Tracy and Bruce Beutler, when they demonstrated that mice injected with TNF exhibited common symptoms of endotoxin poisoning, such as hypotension, metabolic acidosis, hemoconcentration, and death. [22]
In 1991, Michael Goodman demonstrated that mice injected with TNF released increased levels of tyrosine and 3-methyl-L-histidine in their skeletal muscles, indicating that TNF induces muscle breakdown. [23] In 1996, Stefferl et al. demonstrated that mice injected with mouse TNF develop fevers, definitively demonstrating that TNF is a pyrogen. Previous studies showed inconclusive results due to the use of human TNF, rather than mouse TNF, on mice. [24]
The observation that TNF induces wasting and endotoxic shock led to rethinking about its potential role as a cancer therapy. [17]
In September 1981, Masanobu Kawakami and Anthony Cerami investigated the tendency of bacteria endotoxins to induce hypertriglyceridemia, caused by a deficiency of lipoprotein lipase (LPL), when administered to animals. They extracted serum from donor mice injected with endotoxin and injected the serum into recipient mice. They discovered that endotoxin-resistant recipient mice had decreased LPL activity after receiving the serum of endotoxin-treated mice, even though their LPL activities were not markedly reduced when injected with endotoxin directly. The authors also discovered that exudate cells, consisting mostly of macrophages, when incubated with endotoxins, produced a medium that lowered LPL activity when injected into mice. The authors deduced that hypertriglyceridemia was caused by a mediating factor, termed cachectin, secreted by exudate cells in response to endotoxins. [25]
In 1985, Beutler et al. demonstrated that mouse cachectin has similar cytotoxicity against L-929 cells as TNF, as well as a near identical N-terminal amino acid sequence to human TNF, indicating that cachectin and TNF were the same protein. Since cachectin (now TNF) is known to suppress the biosynthesis of a specific protein, lipoprotein lipase, the authors deduced that TNF's cytotoxic mechanism operated in a similar way. [26]
In 1968, lymphotoxin, a cytotoxin secreted by lymphocytes, was discovered. Both TNF and lymphotoxin were detected based on their ability to kill L-929 cells, were able to bind to the two known TNF receptors, TNFRI and TNFRII, and shared significant genetic and amino acid homology. The similarities between TNF and lymphotoxin led to the unofficial renaming of TNF to TNF-α and lymphotoxin to TNF-β, with the published rationale being that they are detected with the same in vitro assays. [17]
In 1993, lymphotoxin, which is not a transmembrane protein, was discovered to be present on the cell membrane by forming a complex with a separate transmembrane glycoprotein, termed lymphotoxin-β. [27] Lymphotoxin was also discovered to play a critical role in the development of lymphoid organs, distinguishing its biological function from TNF. As a result of these developments, TNF-β was renamed to lymphotoxin-α, and TNF-α was renamed back to TNF. [17]
The human TNF gene is mapped to chromosome 6p21.3, residing in the Class III region of the Major Histocompatibility Complex. It is 250 kilobases centromeric of the HLA-B locus, 850 kilobases telomeric of the HLA-DR, and 1,100 base pairs downstream of the lymphotoxin-α gene.[28] The TNF gene is 2,762 base pairs long and results in a mature mRNA consisting of 1,669 nucleotides.[29] The proximal promoter region is approximately 200 base pairs long.[30]
The transcribed region contains 4 exons separated by 3 introns, for a total of 2,762 base pairs in the primary transcript, and 1,669 base pairs in the mRNA. The first exon contains the 5' untranslated region and the major portion of the signal peptide of precursor TNF. The second exon contains the minor region of the signal peptide and a minor region of the coding region of mature TNF. The third exon contains a minor region of the coding region. The fourth exon contains the major portion of the coding region and the 3' untranslated region, and shares significant homology with lymphotoxin-α.[31]
The 3' untranslated region contains an AU-rich element (ARE) that regulates translational repression and mRNA stability. Deletion of this sequence in mice leads to increased TNF levels, arthritis, and a "Crohn's-like" phenotype.
The TNF gene is expressed in a wide range of cells, including macrophages, T cells, B cells, Natural Killer cells, mast cells, dendritic cells, and fibroblasts.[30]
The TNF gene is also an immediate early response gene; it is activated rapidly in response to stimuli and does not depend on the synthesis of other proteins. Such stimuli include endotoxins from bacteria, substances from viruses and protozoans, ionophores, single-stranded and double-stranded RNA, mitogens, superantigens, anti-CD3, polyhydroxyalkanoates, and silica particles. These stimuli bind to a range of receptors, including including Toll-like receptor, NOD2, T-cell receptor, B-cell receptor, Mast cell receptor, and NK cell receptor. TNF is also activated by other cytokines, such as Interleukin-1, Interleukin-2, GM-CSF, and TNF itself, which bind to receptors such as TNFR1 and TNFR2.[32] The TNF gene can also be activated through environmental stresses such as radiation, osmotic stress, and high glucose.[30]
These stimuli activate pathways such as NF-κB[33], Caspase-1[34], and the MAPK[35] pathways, which activate transcription factors such as NF-κB, NFAT, c-jun, ATF-2, Ets, Elk-1, and Sp1. These transcription factors translocate to the nucleus to begin TNF transcription.[30]
TNF gene expression is regulated through enhanceosomes, where multiple transcription factors and coactivators assemble into high-order structures to activate transcription. The proximal promoter region, spanning approximately 200 base pairs before the transcribed region, contains multiple transcription factor binding sites, many of which can recognize more than one type of transcription factor.[30]
The composition of the enhanceosome depends on the ambient concentration of NFAT in the nucleus. If NFAT levels are high, such as in T cells upon ionomycin stimulation, the enhanceosome will consist mostly of NFATs bound at NFAT binding sites. If NFAT levels are low, the enhanceosome will consist mostly of Sp1 and Ets/Elk proteins bound at compatible binding sites.[30]
Additionally, the proximal promoter region contains a cyclic AMP response element (CRE), a binding site for the heterodimer of proteins ATF-2 and c-jun, that is critical for the activation of TNF in all cell-types and conditions. The CRE and nearby transcription factor complexes form the core composite complexes, which interact with other anchor complexes to stabilize interactions with coactivators and transcription machinery. The proximal promoter region also contains a TATA box to assist with transcription.[30]
The flexibility of the enhanceosome composition enables the TNF gene to be activated by different transcription factors depending on the cell type and stimulus.[30]
The transcription factor NF-κB has been shown to play an important role in regulating the gene expression of TNF. However, it is unclear whether NF-κB activates TNF transcription by binding directly to sites in the promoter region, or through secondary effects.[30]
Of the six sequences identified as potential NF-κB binding sites in the human TNF promoter region, only 1 is in the proximal promoter region. Furthermore, the deletion or mutation of these binding sites does not affect the activation of the TNF gene by endotoxin induction, indicating that NF-κB may not influence TNF expression by directly binding to the promoter.[30]
Other transcription factors have been found to potentially influence TNF gene expression, such as proteins of the bZIP, STAT, and IRF families, as well as endotoxin-induced TNF-α factor (LIPAF). However, their effect on TNF gene expression is yet to be fully studied.[30]
TNF gene expression is associated with multiple histone acetyltransferases, proteins that relax the DNA structure to increase gene expression, such as ATF-2, CBP/p300, p/CAF, and GCN5. Histone methylation has also been shown to regulate TNF gene expression, such as the methylation of lysine 4 of histone H3 at the TNF promoter following stimulation of TNF-expressing cells.[30]
TNF gene expression is also controlled by the presence of DNase-hypersensitive sites (HSSs), regions of chromatin that are uncondensed and thus accessible to DNA-binding proteins. Several studies have shown that HSSs are present at the TNF promoter and gene region in cells that express TNF, and absent in cells that do not express TNF. Other studies have also shown that HSSs are present in the TNF promoter and gene regions depending on the stimulant used to induct the cell.[30]
Long range intrachromosomal and interchromosomal interactions have also been found to regulate TNF gene expression. For example, in activated T cells, the TNF promoter interacts with HSS+3 and HSS-9, bringing distal enhancers closer to the TNF promoter and increasing the local concentration of enhancer complexes. These interactions would also circularize the TNF gene and allow for the recycling of transcription machinery, enabling the rapid and early expression of TNF in T cells.[30]
The TNF and lymphotoxin-α genes are believed to be descended from a common ancestor gene that developed early in vertebrate evolution, before the Agnatha / Gnathostomata split. This ancestor gene was dropped from the Agnatha ancestor, but persisted in the Gnathostomata ancestor. During the evolution of gnathostomes, this ancestor gene was duplicated into the TNF and lymphotoxin-α genes.[36]
Thus, while the TNF/lymphotoxin-α ancestor gene is found across a variety of gnathostome species, only a subset of gnathostome species contain a TNF gene. The TNF gene has been found in fish, mammals, birds, and amphibians. Some fish species, such as Danio, have been found to contain duplicates of the TNF gene.[36]
The TNF gene is very similar among mammals, ranging from 233 to 235 amino acids.[37] The TNF proximal promoter region is also highly conserved among mammals, and nearly identical among higher primates.[30] The similarity of the TNF gene among fish is lower, ranging from 226 to 256 amino acids. Like mammalian TNF, the fish TNF gene has been shown to be stimulated in macrophages by antigens.[37] All TNF genes have a highly conserved C-terminal module known as the TNF homology domain, due to its important role in binding TNF to its receptors.[36]
TNF is primarily produced as a 233-amino acid-long type II transmembrane protein arranged in stable homotrimers.[38] [39] From this membrane-integrated form the soluble homotrimeric cytokine (sTNF) is released via proteolytic cleavage by the metalloprotease TNF alpha converting enzyme (TACE, also called ADAM17).[40] The soluble 51 kDa trimeric sTNF tends to dissociate at concentrations below the nanomolar range, thereby losing its bioactivity. The secreted form of human TNF takes on a triangular pyramid shape, and weighs around 17-kDa. Both the secreted and the membrane bound forms are biologically active, although the specific functions of each is controversial. But, both forms do have overlapping and distinct biological activities.[41]
The common house mouse TNF and human TNF are structurally different.[42] The 17-kilodalton (kDa) TNF protomers (185-amino acid-long) are composed of two antiparallel β-pleated sheets with antiparallel β-strands, forming a 'jelly roll' β-structure, typical for the TNF family, but also found in viral capsid proteins.
TNF exerts several actions on various organ systems, often in conjunction with IL-1 and interleukin-6 (IL-6). In the hypothalamus, TNF stimulates the hypothalamic-pituitary-adrenal axis by promoting the release of corticotropin releasing hormone (CRH), suppressing appetite, and inducing fever. In the liver, TNF stimulates the acute phase response, leading to an increase in C-reactive protein and other mediators. Additionally, TNF induces insulin resistance by promoting serine-phosphorylation of insulin receptor substrate-1 (IRS-1), which impairs insulin signaling.
TNF also acts as a potent chemoattractant for neutrophils and promotes the expression of adhesion molecules on endothelial cells, facilitating neutrophil migration. In macrophages, TNF stimulates phagocytosis, as well as the production of IL-1, oxidants, and the inflammatory lipid prostaglandin E2 (PGE2). TNF increases insulin resistance in other tissues by phosphorylating serine residues on insulin receptors, thereby blocking signal transduction. Furthermore, TNF plays a role in regulating bitter taste perception, influencing metabolism and food intake.[43]
A local increase in TNF concentration triggers the cardinal signs of inflammation: heat, swelling, redness, pain, and loss of function.
TNF can bind two receptors, TNFR1 (TNF receptor type 1; CD120a; p55/60) and TNFR2 (TNF receptor type 2; CD120b; p75/80). TNFR1 is 55-kDa and TNFR2 is 75-kDa.[44] TNFR1 is expressed in most tissues, and can be fully activated by both the membrane-bound and soluble trimeric forms of TNF, whereas TNFR2 is found typically in cells of the immune system, and responds to the membrane-bound form of the TNF homotrimer. As most information regarding TNF signaling is derived from TNFR1, the role of TNFR2 is likely underestimated. At least partly because TNFR2 has no intracellular death domain, it shows neuroprotective properties.[45]
Upon contact with their ligand, TNF receptors also form trimers, their tips fitting into the grooves formed between TNF monomers. This binding causes a conformational change to occur in the receptor, leading to the dissociation of the inhibitory protein SODD from the intracellular death domain. This dissociation enables the adaptor protein TRADD to bind to the death domain, serving as a platform for subsequent protein binding. Following TRADD binding, three pathways can be initiated.[46] [47]
The myriad and often-conflicting effects mediated by the above pathways indicate the existence of extensive cross-talk. For instance, NF-κB enhances the transcription of C-FLIP, Bcl-2, and cIAP1 / cIAP2, inhibitory proteins that interfere with death signaling. On the other hand, activated caspases cleave several components of the NF-κB pathway, including RIP, IKK, and the subunits of NF-κB itself. Other factors, such as cell type, concurrent stimulation of other cytokines, or the amount of reactive oxygen species (ROS) can shift the balance in favor of one pathway or another. Such complicated signaling ensures that, whenever TNF is released, various cells with vastly diverse functions and conditions can all respond appropriately to inflammation. Both protein molecules tumor necrosis factor alpha and keratin 17 appear tobe related in case of oral submucous fibrosis[50]
In animal models TNF selectively kills autoreactive T cells.[51]
There is also evidence that TNF-α signaling triggers downstream epigenetic modifications that result in lasting enhancement of pro-inflammatory responses in cells.[52] [53] [54] [55]
This protein may use the morpheein model of allosteric regulation.[56]
Large amounts of TNF are released in response to lipopolysaccharide (LPS), other bacterial products, and interleukin-1 (IL-1). In the skin, mast cells are the predominant source of pre-formed TNF, which can be released upon inflammatory stimuli such as LPS.[57]
While high concentrations of TNF can induce shock-like symptoms, prolonged exposure to low concentrations may lead to cachexia, a wasting syndrome often observed in cancer patients.
TNF causes an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes. This leads to IL-10 production by monocytes after the binding of PD-1 by PD-L.[58]
TNF increases in response to sepsis is inhibited by exercise-induced production of myokines. To investigate whether acute exercise induces a true anti-inflammatory response, a model of 'low-grade inflammation' was used. In this model, a low dose of E. coli endotoxin was administered to healthy volunteers, who were randomized to either rest or exercise prior to endotoxin administration. In resting subjects, endotoxin induced a 2- to 3-fold increase in circulating TNF levels. However, when subjects performed three hours of ergometer cycling and received the endotoxin bolus at 2.5 hours, the TNF response was completely blunted.[59] Acute exercise may inhibit TNF production.[60]
In the brain, TNF can protect against excitotoxicity, strengthen synapses, and promote neuronal survival. However, TNF produced by macrophages and microglia can result in the production of neurotoxins that induce apoptosis.
Increased concentrations of TNF-α and IL-6 are associated with obesity.[61] [62] [63] The use of monoclonal antibodies against TNF-α is paradoxically associated with increases rather than decreases in obesity, suggesting that inflammation is a consequence rather than a cause of obesity.[63] TNF and IL-6 are among the most prominent cytokines predicting the severity and mortality of COVID-19.
TNFα mediates the inflammation that activates resident Hepatic Stellate Cells (HSCs) into the fibrogenic myofibroblasts that are largely responsible for liver fibrosis. However, whereas TNF receptor 1 knock-out mice demonstrate reduced fibrosis, TNFα can also suppress collagen α1(I) gene expression in fibroblasts in vitro, raising questions in regard to the complexity of its role in liver fibrosis.[64]
While TNFα treatment suppresses collagen α1 gene expression, apoptosis, and proliferation in activated HSCs in vitro, an activity that should ameliorate fibrosis, it has also been shown to inhibit apoptosis in activated HSCs, an activity which should, in principle, induce fibrosis.[65] Specifically, TNFα produced by hepatic macrophages is known to support the survival of HSCs, the source of hepatic myofibroblasts.[66] TNFα is therefore believed to promote liver fibrosis through its pro-survival effect, despite its pleiotropic effects on HSCs.[67]
Yet another way TNFα contributes to the worsening of liver fibrosis is by stimulating the production of TGF-β by hepatocytes and TIMP1 by hepatocytes and HSCs.[68]
It should furthermore be noted that CCR9+ macrophages, which play an essential role in the pathogenesis of liver fibrosis, are TNFα-dependent. When TNFα is attenuated using an anti-TNFα antibody, hepatic HSCs are not activated by CCR9+ macrophages.[69]
TNFα has a dual role in the development of NAFLD. Firstly, it is released among other pro-inflammatory cytokines, such as IL-6 and IL-1β, in response to the increased signaling from NF-κB during steatosis. TNFα then participates in the recruitment of Kupffer cells, which increase inflammation and lead to the development of NASH.[70]
Secondly, the binding of TNFα to TNFα receptor 1 (TNFR1) facilitates insulin resistance, a known contributor to NAFLD progression, by suppressing insulin signaling.[71] Following the binding of TNF-α to TNFR1, intracellular c-JUN N terminal kinase (JNK) and IkB kinase (IKK) signals are activated, and the phosphorylation of JNK (p-JNK) and IKK1/1KK2 further attenuate insulin receptor substrate 1 (IRS-1). The phosphorylation of IRS-1 leads to the suppression of insulin signaling and, subsequently, to insulin resistance.[72] Blocking TNFR1 protected Wistar rats from diet-induced obesity and insulin resistance.[72]
TNFR1 inhibition has been suggested as a possible therapy for NAFLD. A high-fat diet (HFD) mouse model of NAFLD has been used to demonstrate that the use of an anti-TNFR1-antibody can reduce liver steatosis and triglyceride content, as well as the activation of downstream target genes of lipogenesis. Insulin resistance likewise improved in these mice as a result of the reduced activation of MAP kinase MKK7 and its downstream target JNK.[73]
It is additionally thought that TNFα increases the production of MCP-1 (monocyte chemoattractant protein-1). MCP-1 is known to be overexpressed in obesity and is believed to be responsible for the recruitment of macrophages into adipose tissue and contribute to insulin resistance.[74] The production of MCP-1 increases in primary hepatocytes exposed to TNFα; TNF-α stimulates Mcp1 gene transcription by activating the Akt/PKB pathway.[75]
The dual role of TNFα in the development of NAFLD is counteracted by the anti-inflammatory action of adiponectin, whose production is impaired in metabolic syndrome.[68]
TNFα is, therefore, thought to play a deleterious role in the progression of NAFLD to NASH and cirrhosis.
See main article: TNF inhibitor.
TNF promotes the inflammatory response, which, in turn, causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma. These disorders are sometimes treated by using a TNF inhibitor. This inhibition can be achieved with a monoclonal antibody such as infliximab (Remicade) binding directly to TNF, adalimumab (Humira), certolizumab pegol (Cimzia) or with a decoy circulating receptor fusion protein such as etanercept (Enbrel) which binds to TNF with greater affinity than the TNFR.[76]
On the other hand, some patients treated with TNF inhibitors develop an aggravation of their disease or new onset of autoimmunity. TNF seems to have an immunosuppressive facet as well. One explanation for a possible mechanism is this observation that TNF has a positive effect on regulatory T cells (Tregs), due to its binding to the tumor necrosis factor receptor 2 (TNFR2).[77]
Anti-TNF therapy has shown only modest effects in cancer therapy. Treatment of renal cell carcinoma with infliximab resulted in prolonged disease stabilization in certain patients. Etanercept was tested for treating patients with breast cancer and ovarian cancer showing prolonged disease stabilization in certain patients via downregulation of IL-6 and CCL2. On the other hand, adding infliximab or etanercept to gemcitabine for treating patients with advanced pancreatic cancer was not associated with differences in efficacy when compared with placebo.[78]
TNF has been shown to interact with TNFRSF1A.[79] [80]
Because LTα is no longer referred to as TNFβ,[81] TNFα, as the previous gene symbol, is now simply called TNF, as shown in HGNC (HUGO Gene Nomenclature Committee) database.