TNF-alpha

Multifunctional proinflammatory cytokine that is centrally involved in local and systemic inflammation. TNF-alpha is one of the best-studied members of the so-called TNF/TNFR superfamily, a cytokine system that assumes central functions in the immune response and in organogenesis, particularly in the lymphatic system. It plays a central role in the pathogenesis of psoriasis and other inflammatory processes (Crohn's disease, arthritis; pathogenesis of contact allergy). It causes hemorrhagic necrosis in certain tumors.

TNF-alpha exists biologically in soluble or transmembrane-bound form. TNF-alpha molecules interact with at least 2 receptors (tumor necrosis factor receptor superfamily member 1A(TNFRSF1A) or tumor necrosis factor receptor superfamily member 1B (TNFRSF1B)).

The interaction of TNF-alpha with its receptors activates signaling cascades that can lead to apoptosis (via caspase-8; see caspases below) and cell activation (via NF-κB) (Note: NF-kappaB/nuclear factor-kappa B is a fast-acting primary transcription factor that is present in all cell types. It is involved in cellular responses to stimuli such as cytokines and stress and plays a key role in regulating the immunological response to infections; see also under transcription factors).

The balance of antagonistic effects of both signaling inductions depends on the cellular environment in which stimulation by TNF-alpha occurs. The NF-κB-mediated reaction is relevant for inflammation, in the course of which pro-inflammatory enzymes such as interleukins (especially interleukin-6 and interleukin-8) are released.

TNF-alpha is mainly produced and released by macrophages, but also by a large number of other cells such as lymphocytes, mast cells, endothelial cells, cardiac muscle cells, fibroblasts and neuronal tissue. Large amounts of TNF-alpha are released in response to bacterial products (e.g. lipopolysaccharides) and interleukin-1beta (seeinterleukin-1 below). Its formation is stimulated via Toll-like receptors and the MAPK signaling pathway as well as NF-kappaB. It also has an effect on lipid metabolism, blood coagulation, insulin resistance and various endothelial functions.

TNF-alpha and its receptor interactions are pharmacologically important targets of various drug classes that are used in the biological immunotherapy of various diseases, including Crohn's disease, rheumatoid arthritis and psoriasis. See also infliximab, etanercept, golimumab.

TNF-alpha was described as early as 1975 as a cytokine that plays a role in bacterial diseases.

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