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.
Laboratory test results are the most important parameter for the diagnosis and monitoring of all pathological conditions. 70%-80% of diagnostic decisions are based on laboratory tests. Correct interpretation of laboratory results allows a doctor to distinguish "healthy" from "diseased".
Laboratory test results should not be interpreted from the numerical result of a single analysis. Test results should be interpreted in relation to each individual case and family history, clinical findings and the results of other laboratory tests and information. Your personal physician should explain the importance of your test results.
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