Tumor necrosis factor (TNF), formerly known as TNF-α, is an inflammatory protein and a principal mediator of the innate immune response.[5] TNF is produced primarily by macrophages in response to antigens, and activates inflammatory pathways through its two receptors, tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2).[6] It is a member of the tumor necrosis factor superfamily, a family of type II transmembrane proteins that function as cytokines.[7] Excess production of TNF plays a critical role in the pathology of several inflammatory diseases, and anti-TNF therapies are often employed to treat these diseases.[8]
TNF is expressed primarily by macrophages but is also expressed in several other cell types, such as T cells, B cells, dendritic cells, and mast cells. It is expressed in response to pathogens, other cytokines, and environmental stressors.[9] TNF is initially produced as a type II transmembrane protein (tmTNF) and assembled as a homotrimer, which is then cleaved by TNF alpha converting enzyme (TACE) into a soluble form (sTNF), allowing it to be secreted into the extracellular space.[10] Both tmTNF and sTNF can activate TNFR1, while only tmTNF can activate TNFR2.[6]
TNFR1 can trigger inflammatory pathways, producing effects such as cell survival and proliferation, as well as cell death if the inflammatory pathways are disrupted. TNFR2 can only trigger cell survival and proliferation, but can indirectly induce cell death by disrupting TNFR1.[6] tmTNF also sends reverse signals into its own cell, leading to cell death or survival depending on circumstances.[11] TNF's effects on the immune system include the activation of white blood cells, blood coagulation, secretion of cytokines, and fever, among others.[5] The activity of TNF extends beyond the immune system, such as contributing to homeostasis in the central nervous system.[12]
The excessive production of TNF is known to be a key factor in inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease, and the inhibition of TNF is often an effective treatment.[8] 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.[13] Due to the important role of TNF in innate immunity and homeostasis, the inhibition of TNF can lead to increased risk of infections and new "paradoxical" autoimmunities.[14]
Microbiology(Kaiser)
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