The prototype ligand of the TNF superfamily, TNF-./TNFSF1A, is a pleiotropic cytokine that plays a central role in inflammation and apoptosis . Human cells known to express TNF-. include B cells, colonic columnar epithelial cells, NK and CD3+CD56+ hepatic natural T cells, macrophages, monocytes and monocyte-derived dendritic cells, CD4+ and CD8+ T cells, mast cells, neutrophils, keratinocytes, plasma cells, and adipocytes.

It is synthesized as a 26 kDa, type II transmembrane protein that is 233 amino acids (aa) in length . It contains a 30 aa cytoplasmic domain, a 26 aa transmembrane segment, and a 177 aa extracellular region . TNF-. is assembled intracellularly to form a transmembrane, non-covalently-linked homotrimeric protein. The 157 aa residue soluble form of TNF-. (sTNF-. is released from the C-terminus of the transmembrane protein through the activity of TNF-.-converting enzyme (TACE), a membrane-bound disintegrin metalloproteinase .

TNF-. is reported to promote inflammatory cell infiltration by upregulating leukocyte adhesion molecules on endothelial cells, serve as a chemotactic agent for monocytes, and activate phagocyte killing mechanisms . Deficiencies in either TNF-. or its receptors can increase susceptibility to infection by intracellular pathogens . TNF- may also play a role in lymphoid tissue development. Knockout mice lack splenic B cell follicles and the ability to form germinal centers . Other potential physiological roles for TNF-. and its receptors include regulating the differentiation of hematopoietic stem and progenitor cells .

TNF-. has been implicated in a number of pathophysiological processes. It is associated with unregulated pro-inflammatory activity and is thought to be a critical mediator of endotoxin-induced septic shock . Cachexia (or whole body wasting) has also been associated with long-term circulating TNF-.. Other disorders with potential TNF-. involvement include asthma), type 2 diabetes, CrohnÂ?s disease, and rheumatoid arthritis.