Tumor necrosis factor-alpha

Multifunctional proinflammatory cytokine 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 plays central roles in the immune response and in organogenesis, especially of the lymphatic system. Thus, it plays a central role in the pathogenesis of psoriasis as well as other inflammatory processes (Crohn's disease, arthritides; pathogenesis of contact allergy). It causes hemorrhagic necrosis in certain tumors.

TNF-α exists biologically in soluble or transmembrane-bound form. TNF-α 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-α 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 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 infection/ see also under transcription factors).

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

TNF-α 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 as well as neuronal tissue. Large amounts of TNF-α are released in response to bacterial products (e.g. lipopolysaccharides) as well as interleukin-1β. Its formation is stimulated via Toll-like receptors and the MAP pathway as well as NF-kappaB. Furthermore, it has effects on lipid metabolism, blood coagulation, insulin resistance and various endothelial functions.

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