Tumor necrosis factor alpha (TNF-alpha), is a pleiotropic pro-inflammatory cytokine secreted by various cells, including adipocytes, activated monocytes, macrophages, B cells, T cells and fibroblasts [1, 2]. It belongs to TNF family of ligands, and signals through two receptors, TNFR1 and TNFR2. Human TNF-alpha consisits of a 35 amino acid (aa) cytoplasmic domain, a 21 aa transmembrane segment, and a 177 aa extracellular domain (ECD) [3]. The ECD of human TNF-alpha shares 97% aa sequence identity with rhesus and 71%-92% with bovine, canine, cotton rat, equine, feline, mouse, porcine, and rat TNF-alpha. TNF-alpha is assembled intracellularly to form a noncovalently linked homotrimer which is expressed on the cell surface [4]. Cell surface TNF-alpha can induce the lysis of neighboring tumor cells and virus infected cells, and it can generate its own downstream cell signaling following ligation by soluble TNFR1 [2, 5]. Shedding of membrane bound TNF-alpha by TACE/ADAM17 releases the bioactive cytokine, a 55 kDa soluble trimer of the TNF-alpha extracellular domain [6-8]. TNF-alpha binds the ubiquitous 55-60 kDa TNFR1[9, 10] and the hematopoietic cell-restricted 80 kDa TNFR2 [11, 12], both of which are also expressed as homotrimers [1, 2, 13].
Reference
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