The prototype ligand of the TNF superfamily, TNF-α/TNFSF1A, is a pleiotropic cytokine that plays a central role in inflammation and apoptosis (1-4). Human cells known to express TNF-α 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 (4, 5). It contains a 30 aa cytoplasmic domain, a 26 aa transmembrane segment, and a 177 aa extracellular region (6, 7). TNF-α is assembled intracellularly to form a transmembrane, non-covalently-linked homotrimeric protein. The 157 aa residue soluble form of TNF-α (sTNF-alpha; is released from the C-terminus of the transmembrane protein through the activity of TNF-alpha;-converting enzyme (TACE), a membrane-bound disintegrin metalloproteinase (8, 9).

TNF-alpha; 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 (10). Deficiencies in either TNF-alpha; or its receptors can increase susceptibility to infection by intracellular pathogens (11 - 12). TNF- may also play a role in lymphoid tissue development. Knockout mice lack splenic B cell follicles and the ability to form germinal centers (13, 14). Other potential physiological roles for TNF-alpha; and its receptors include regulating the differentiation of hematopoietic stem and progenitor cells (15 - 17).

TNF-alpha; 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 (18). Cachexia (or whole body wasting) has also been associated with long-term circulating TNF-alpha;. Other disorders with potential TNF-alpha; involvement include asthma), type 2 diabetes, Crohn