TNFA

Official Full Name

tumor necrosis factor

Organism

Homo sapiens

GeneID

7124

Background

This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, psoriasis, rheumatoid arthritis ankylosing spondylitis, tuberculosis, autosomal dominant polycystic kidney disease, and cancer. Mutations in this gene affect susceptibility to cerebral malaria, septic shock, and Alzheimer disease. Knockout studies in mice also suggested the neuroprotective function of this cytokine. [provided by RefSeq, Aug 2020]

Synonyms

DIF; TNFA; IMD127; TNFSF2; TNLG1F; TNF-alpha;

Bio Chemical Class

mRNA target

Protein Sequence

MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTLFCLLHFGVIGPQREEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL

Open

Disease

Crohn disease, Rheumatoid arthritis, Schizophrenia

Approved Drug

10 +

Clinical Trial Drug

33 +

Discontinued Drug

12 +

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Detailed Information

The TNF-α gene is located on chromosome 6p21.4, encompassing a region approximately 3.6 kb in length. Specifically between the HLA-B and HLA-C2 loci inside the MHC Class III region, it comprises four exons and three introns and is strongly connected to the main histocompatibility complex (MHC) genes. TNF-α was first discovered by Carswell et al., who injected pre-sensitized mice, pre-activated with Bacillus Calmette-Guérin (BCG), with lipopolysaccharide (LPS) to produce a serum factor effective of triggering hemorrhagic necrosis in tumors. Later on, given its actions, this element was dubbed tumor necrosis factor (TNF).

Regarding cellular expression, studies have shown that natural killer (NK) cells, T lymphocytes, and activated macrophages generate TNF-α mainly. With significant expression also detected in lymph nodes, appendix, endometrium, lung, and spleen, RNA sequencing studies of 27 human tissues have indicated the greatest expression of TNF in bone marrow. TNF-α's controlled expression emphasizes its function in both normal immune responses and disease states.

TNF-alpha Protein Structure and Forms

Two main types of TNF-α are a soluble TNF-α (sTNF-α) and a transmembrane TNF-α (tmTNF-α). Originally synthesized as a membrane-bound protein, transmembrane TNF-α, the precursor form, has 233 amino acids. Cleavage by TNF-α converting enzyme (TACE releases the 157 amino acid soluble form). Both versions are physiologically active and work via homotrimeric complexes. TNF-α's unique cone-shaped trimeric structure, each monomer made of two closely spaced β-sheets. A jelly-roll structure is essential for its action.

TNF-alpha Receptors and Signaling Pathways

By interacting with two different receptors—TNFR1 and TNFR2—TNF-α generates its biological effects. Members of the TNF receptor superfamily, both receptors control many signaling pathways essential for immune responses, cell survival, and death.

Ten exons make up TNFR1, a 55–60 kDa transmembrane receptor carried on chromosome 12p13.31. Comprising a death domain (DD), which is essential for apoptosis, the TNFR1 receptor can bind both sTNF-α and tmTNF-α. The DD conformally changes when TNF-α binds to TNFR1, attracting signaling molecules including TNFR1-associated death domain (TRADD) and receptor-interacting protein kinase 1 (RIPK1), therefore generating distinct signaling complexes. These complexes subsequently activate downstream pathways including NF-kappaB and MAPKs, therefore producing inflammation, cell survival, proliferation, and immunological defense. Whereas complex IIc activates mixed-lineage kinase domain-like protein (MLKL), which causes necrosis, complexes IIa and IIb activate caspase-8, hence initiating death.

Conversely, TNFR2 lacks a death domain and is essentially triggered by tmTNF-α. Rather, it activates NF-kappaB, MAPKs, and AKT signaling pathways using tumor necrosis factor receptor-associated factors (TRAFs), most especially TRAF1 and TRAF2. Cell survival, cell proliferation, and tissue regeneration all depend on these mechanisms. Particularly TNFR2 is linked to the preservation of cellular homeostasis and is involved in regulatory mechanisms including tissue repair and survival in inflammatory surroundings.

Figure 1 illustrates the signaling pathways of TNFR1 and TNFR2 activated by TNF-α, highlighting their roles in processes such as inflammation, cell survival, apoptosis, necroptosis, and tissue regeneration. Figure 1. Tumor necrosis factor alpha (TNF-α) signaling pathways of TNFR1 and TNFR2. (Jang DI et al., 2021)

TNF-alpha's Role in Physiological and Pathological Conditions

A necessary component of the normal immune response, TNF-α controls bodily defenses. However, overproduction of TNF-α may have negative consequences and help certain inflammatory and autoimmune illnesses develop. Rheumatoid arthritis (RA) is one well-known disorder where TNF-α is mostly important.

Mostly defined by inflammation in many joints, RA is a chronic inflammatory disease that causes symptoms like joint discomfort, fever, and swelling. Severe forms of RA could cause limited mobility and irreversible joint degeneration. With raised levels seen in RA sufferers, TNF-α is regarded as a vital cytokine in the pathophysiology of this condition. Th1 helper cells and macrophages both of which are major TNF-α producers induce inflammatory cell increase in RA.

Under TNF-α, activated fibroblast-like synoviocytes increase the production of tissue-degrading enzymes including matrix metalloproteinases (MMPs). Cartilage and bone therefore break down, which causes joint erosion. Activated in reaction to TNF-α, osteoclasts—the bone-resorbing cells—also help to accelerate the pathologic development of RA. Furthermore very important for disease progression are synovial hyperplasia and angiogenesis, activities encouraged by TNF-α. TNF-α finally stimulates fibroblasts, which help to deposit and break down collagen, therefore promoting joint injury and fibrosis.

TNF-alpha in Autoimmune Disease Treatments

TNF-α is fundamental in the pathophysiology of autoimmune diseases, so TNF-α inhibitors have become rather important in treating disorders like RA, Crohn's disease (CD), bronchial asthma (BA), systemic lupus erythematosus (SLE), and psoriasis. Among the most well-known TNF-α inhibitors are monoclonal antibodies including adalimumab, golimumab, certolizumab, etanercept, and infliximab. These biologics neutralize TNF-α activity, therefore lowering inflammation, and stopping the spread of illness.

Therapeutic approaches that have lately advanced are increasing the range of available treatments. Targeting both TNF-α and interleukin-6 (IL-6) greatly enhanced treatment results for RA patients, according to a research team at Sanofi's Science Translational Medicine paper from 2023. By concurrently inhibiting these two important inflammatory pathways, the scientists created a TNF-IL-6 bispecific nanobody with significant promise for treating RA. Representing a great development in autoimmune disease treatment, this dual-targeting method is ready for clinical testing.

References:

Akdis M, Aab A, Altunbulakli C, et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2016;138(4):984-1010.
Jang DI, Lee AH, Shin HY, et al. The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics. Int J Mol Sci. 2021;22(5):2719.
Lin YJ, Anzaghe M, Schülke S. Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis. Cells. 2020;9(4):880.
Biesemann N, Margerie D, Asbrand C, et al. Additive efficacy of a bispecific anti-TNF/IL-6 nanobody compound in translational models of rheumatoid arthritis. Sci Transl Med. 2023;15(681):eabq4419.

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