TNF proteins

Tumor necrosis factors also known as TNFs are a family of proteins secreted predominantly by immune cells. They are involved in cell signaling and are involved in regulating diverse cell functions such as inflammation, mediated immune response, proliferation, differentiation, apoptosis, and embryogenesis. The first two members of the family to be identified were: Tumor Necrosis Factor Alpha (TNF Alpha) and Tumor necrosis factor-beta (TNF-β). TNF Alpha is an inflammatory cytokine produced mainly by macrophages. This protein is responsible for a number of signaling pathways that eventually lead to cell necrosis or apoptosis. TNF alpha exerts its effect by binding to its receptor as a trimer.

Tumor necrosis factor receptors or TNFRs are a family of proteins that are involved in signaling pathways responsible for cell survival, cell differentiation or cell death. TNF family of receptors regulates the development of immune system and the initiation of the inflammatory response against bacterial and viral pathogens. Mutations of the TNFRs family of proteins have been linked to impaired immune response and have been associated with a number of autoimmune conditions. For this reason, TNFRs are often considered as a potential target for drug intervention. TNFRs family consists of 27 members. Tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2) are one of the few members of TNFR superfamily. They have the ability to bind to TNF ligand. TNF1 is found in most tissues and can be activated by both membrane-bound and soluble trimeric form of TNF. TNFR2 is found typically in cells of the immune system and responds to the membrane-bound form of the TNF homotrimer.

Once in contact with their ligand, TNF receptors also form trimers. This binding causes a conformational change to occur in the receptor that leads to the activation of the signalling pathways.

There has been a gradual realization of the value of TNF/TNFR ratios as predictors of disease outcome, and the discovery of functional regulatory polymorphisms of the TNF gene and mutations of TNFRSF1A (TNFR1 receptor) have led to conceptual breakthroughs in the understanding of the genetic control of inflammation. TNF and TNFR impaired activations has been linked to several autoimmune conditions. Due to their key role in apoptosis, TNF/TNFR are considered as a potential anti-cancer therapy although much work is required to reduce their toxicity.