Tumor necrosis factor alpha (TNF-alpha, TNF- alpha, TNFA ), also
known as Cachectin and TNFSF2, is the prototypic ligand of the TNF superfamily.
It is a pleiotropic molecule that plays a central role in inflammation, immune
system development, apoptosis, and lipid metabolism. TNF-alpha is produced by
several lymphoid cells as well as by astrocytes, endothelial cells, and smooth
muscle cells. Mouse TNF-alpha consists of a 35 amino acid (aa) cytoplasmic
domain, a 21 aa transmembrane segment, and a 179 aa extracellular domain (ECD).
Within the ECD, mouse TNF-alpha shares 94% aa sequence identity with rat and 70%-77%
with bovine, canine, cotton rat, equine, feline, human, porcine, and rhesus
TNF-alpha. TNF-alpha is produced by a wide variety of immune, epithelial,
endothelial, and tumor cells. TNF-alpha is assembled intracellularly to form a
noncovalently linked homotrimer which is expressed on the cell surface. 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 TNFR I. Shedding of membrane bound TNF-alpha by TACE/ADAM17
releases the bioactive cytokine, a 55 kDa molecular weight soluble trimer of
the TNF-alpha extracellular domain. TNF-alpha binds the ubiquitous 55-60 kDa
TNF RI and the hematopoietic cell-restricted 80 kDa TNF RII, both of which are
also expressed as homotrimers present on virtually all cell types. Both type I
and type II receptors bind TNF-alpha with comparable affinity, although only
TNF RI contains a cytoplasmic death domain which triggers the activation of
apoptosis. Soluble forms of both types of receptors are released and can
neutralize the biological activity of TNF-alpha.