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Tumor Necrosis Factor α (TNF-α)

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Tumor necrosis factor α (TNF-α) is a multifunctional cytokine that participates in many different pathways in mammalian homeostasis and pathophysiology. It may be involved in counteracting biological actions, which means complex regulatory mechanisms. TNF-α, also known as cachectin, was first identified as a cytotoxic agent that causes lysis of certain cancer cells. The TNF-α gene is a member of the TNF-α superfamily (consisting of at least 20 different members). TNF-α plays a central role in inflammation, immune system development, apoptosis and lipid metabolism. TNF-α is also involved in a number of pathological conditions including asthma, Crohn's disease, rheumatoid arthritis, neuropathic pain, obesity, type 2 diabetes, septic shock, autoimmunity and cancer.

The release of TNF-α is primarily caused by viral infections and endotoxins, lipopolysaccharides or other bacterial constituents, tissue injury, DNA damage and by IL-1, PDFG and TNF-α itself. It is mainly produced by macrophages, but also by monocytes, neutrophils, NK cells, mast cells, endothelial cells and activated lymphocytes. Expression of TNF-α in endothelial cells and fibroblasts is induced by IL-17. Expression of other cytokines, chemokines, reactive oxygen radicals, nitric oxides and prostaglandins are stimulated by TNF-α.

Initially, membrane-bound TNF-α is enzymatically cleaved by TACE (ADAM17). Soluble monomers are aggregated into homotrimers and excreted in blood and other biological fluids. Membrane-bound and soluble forms of TNF-α are biologically active and bind to TNF-α receptors, TNFR1 (TNFRSF1A, p55-60) and TNFR2 (TNFRSF1B, TNFBR2, p75-80). Upon binding of TNF-α, the receptors form trimers and lead to conformational changes that ultimately result in the following biological actions:

  • Transcription of anti-apoptotic factors and proteins involved in cell proliferation and inflammation by binding to TRAF2 (TNF-R associated factor 2) and RIPK1 (TNF-R interacting serine-threonine kinase 1) and activating factor of NF-κB transcription.
  • Cell proliferation, differentiation, but also apoptosis (cell death) through binding to TRAF2.
  • Apoptosis through FADD binding (caspase 8 activation) and activation of caspases (including caspase 8).
  • Necrosis, the death of a cell with a caspase-independent mechanism, induced by NADPH oxidases leading to the production of reactive oxygen radicals.

Thus, the multiple biological functions of TNF-α include cell proliferation and differentiation, oncogenesis, apoptotic or necrotic cell death, immunomodulatory functions, lipid metabolism, thrombosis and endothelial function. It promotes local or systemic inflammation (TNF-α is a potent pyrogen) and stimulates the acute phase response. High concentrations of TNF-α after infection can lead to septic shock (TNF-α is highly cytotoxic), while low levels induce cachexia and inflammation.

Deregulation of TNF-α is involved in many diseases:

Cancer: Different roles of TNF-α in cancer have been described, depending on the type of tumor and the microenvironment of the tumor. According to one hypothesis, very high levels of TNF-α lead to tumor recession while its chronic low concentration is associated with tumor progression.

Systemic lupus erythematosus (SLE): SLE mouse models show contradictory effects on TNF-α: low autoantibody TNF-α (TNF-α administration attenuates symptoms and excludes SLE symptoms), pre-inflammatory action at high levels of TNF-α.

Chronic inflammatory bowel disease (Crohn's disease, ulcerative colitis): The contribution of TNF-α / TNF-R1 activity to induction of chronic intestinal inflammation and the overexpression of TNF-α in monocytes and macrophages has been described.

Psoriasis: In psoriatic patients, TNF-α appears to increase both systemically and in dermal tissue. Expression of TNF-α in peripheral blood mononuclear cells (PBMCs) was highly increased in patients with active phase of the disease and increased in chronic psoriasis. In animals, TNF-α activation of T cells has been shown to be essential for the development of psoriasis.

Pulmonary disorders (cystic fibrosis, asthma): High levels of TNF-α were observed in cystic fibrosis. TNF-α is over-expressed in persistent severe asthma. In allergic asthma, with low antigen exposure, TNF-α contributes to increased histamine release. In experimental animals, inflammation of the airways was induced by TNF-α-mediated phospholipase A2 activation.

Rheumatoid arthritis, ankylosing spondylitis: TNF-α has stimulatory effects on the core degradation proteases (metalloproteinases, MMPs), tissue remodeling, and osteoclasts, causing bone resorption. In a mouse model for rheumatoid arthritis, elevated levels of TNF-α were observed in the bone marrow. Cytokines synthesized by articular cells after TNF-α activation have been shown to induce rheumatoid arthritis. In patients with ankylosing spondylitis, the concentration of TNF-α is elevated in the sacroiliac joint.

Transplantation (graft versus host disease, allograft rejection): Measurement of TNF-α has been shown to be useful in transplantation research. TNF-α is significantly increased in renal allograft rejection. Also, elevated levels of TNF-α have been reported in bone marrow transplantation. Transplanted patients with major transplant-related complications, such as interstitial pneumonitis and severe acute graft versus host disease, showed significantly elevated levels of TNF-α.

Atherosclerosis, arterial calcification: Increased risk of recurrence of myocardial infarction, atherosclerotic thickening of the carotid artery, disorders of triglyceride and glucose homeostasis, and age-related atherosclerosis. TNF-α induces mechanisms leading to increased calcium deposition in the aorta in animals with type 2 diabetes mellitus.

Insulin resistance and obesity: Increased expression of TNF-α in adipose tissue has been observed in animal models of obesity. Elevated levels of TNF-α affect the biochemical pathway of insulin regulation.

Neurodegenerative diseases (multiple sclerosis, Alzheimer's disease, Parkinson's): TNF-α is produced by activated microglial cells and leads to neuronal degeneration, neural tissue apoptosis and increased inflammation. Administration of TNF-α caused the death of oligodendrocytes - a symptom of multiple sclerosis - in in vitro experiments.




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