What is TNF Alpha?
Definition: Tumor Necrosis Factor or TNF alpha is a cytokine, a cell signalling protein which acts as a central regulator of inflammation. The majority of TNF alpha is produced by macrophages but a wide variety of other cell types can also produce it.
TNF alpha exists as a transmembrane protein arranged in stable homotrimers. A soluble form of TNF alpha can be produced by proteolytic cleavage of the membrane bound form. Both forms are biologically active although the specific function of each is controversial.
TNF alpha is recognised by two main receptors: TNFR1 (TNF Receptor 1, CD120a) and TNFR2 (TNF Receptor 2, CD120b.
TNFR1 is expressed by most tissues and can be activated by both forms of TNF alpha. TNFR2 is mainly expressed in the immune system and responds to the membrane bound form of TNF alpha. Binding of TNF alpha to TNFR1 results in conformation changes in the receptor and recruitment of TRADD, this in turn binds FADD, TRAF2 and RIP and results in activation of downstream pathways such as, NF-κB, JNK and p38 MAPK pathways and death signalling. The NF-κB and MAPK pathways induce complex and long lasting transcriptional modifications and the production of interleukins and chemokines
TNF alpha signalling is an essential part of the immune system as inhibits tumorigenesis, prevents viral replication and is an endogenous pyrogen inducing fever and apoptosis. Dysregulation of this pathway has been implicated in a variety of disorders including cancer, autoimmune diseases, Alzheimer’s disease and depression. Various anti-TNF drugs have been approved for the treatment of inflammatory related diseases including rheumatoid arthritis, Crohn's disease and psoriasis.
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