Tumor necrosis factor

Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors on other cells. It is a member of the tumor necrosis factor superfamily, a family of transmembrane proteins that are cytokines, chemical messengers of the immune system. Excessive production of TNF plays a critical role in several inflammatory diseases, and TNF-blocking drugs are often employed to treat these diseases.

TNF is produced primarily by macrophages but is also produced in several other cell types, such as T cells, B cells, dendritic cells, and mast cells. It is produced rapidly in response to pathogens, cytokines, and environmental stressors. TNF is initially produced as a type II transmembrane protein (tmTNF), which is then cleaved by TNF alpha converting enzyme (TACE) into a soluble form (sTNF) and secreted from the cell. Three TNF molecules assemble together to form an active homotrimer, whereas individual TNF molecules are inert.

When TNF binds to its receptors, tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2), a pathway of signals is triggered within the target cell, resulting in an inflammatory response. sTNF can only activate TNFR1, whereas tmTNF can activate both TNFR1 and TNFR2, as well as trigger inflammatory signaling pathways within its own cell. TNF's effects on the immune system include the activation of white blood cells, blood coagulation, secretion of cytokines, and fever. TNF also contributes to homeostasis in the central nervous system.

Inflammatory diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease can be effectively treated by drugs that inhibit TNF from binding to its receptors. TNF is also implicated in the pathology of other diseases including cancer, liver fibrosis, and Alzheimer's, although TNF inhibition has yet to show definitive benefits.

In the 1890s, William Coley observed that acute infections could cause tumor regression, leading to his usage of bacterial toxins as a cancer treatment. In 1944, endotoxin was isolated from Coley's bacterial toxins as the substance responsible for the anticancer effect. In particular, endotoxin could cause tumor regression when injected into mice with experimentally induced cancers. In 1975, Carswell et al. discovered that endotoxin did not directly cause tumor regression, but instead induced macrophages to secrete a substance that causes tumors to hemorrhage and necrotize, termed "tumor necrosis factor."

In the 1980s, TNF was purified, sequenced, and cloned in bacteria. Studies on recombinant TNF confirmed the anticancer potential of TNF, but this optimism faded when TNF injections were found to induce endotoxin shock. TNF was also discovered to be the same protein as cachectin, known to cause muscle wasting in mice. These findings demonstrated that TNF could be detrimental in excessive quantities. In 1992, TNF antibodies were found to reduce joint inflammation in mice, revealing TNF's role in inflammatory diseases. This led to the approval of the first anti-TNF therapy for rheumatoid arthritis in 1998.

In 1985, TNF was found to have significant sequential and functional similarity with lymphotoxin, a previously discovered cytokine. This led to the renaming of TNF to TNF-α and lymphotoxin to TNF-β. However, in 1993, a protein with close similarity to lymphotoxin was discovered, termed lymphotoxin-β. In 1998, at the Seventh International TNF Congress, TNF-β was officially renamed to lymphotoxin-α, while TNF-α was renamed back to TNF. Nevertheless, some papers continue to use the term TNF-α.

The TNF and lymphotoxin-α genes are believed to be descended from a common ancestor gene that developed early in vertebrate evolution, before the Agnatha and Gnathostomata split. This ancestor gene was dropped from the Agnatha ancestor but persisted in the Gnathostomata ancestor. During the evolution of gnathostomes, this ancestor gene was duplicated into the TNF and lymphotoxin-α genes. Thus, while the ancestor gene is found across a variety of gnathostome species, only a subset of gnathostome species contain a TNF gene. Some fish species, such as Danio, have been found to contain duplicates of the TNF gene.