Rat TNF-alpha is synthesized as a 26 kDa type II transmembrane
protein that consists of a 35 amino
acid (aa) cytoplasmic domain, a 21 aa transmembrane segment,
and a 156 aa extracellular
domain (ECD) (12). Within the ECD, rat TNF-alpha shares 95% aa
sequence identity with mouse, and
73% - 79% aa identity with bovine, canine, cotton rat,
equine, feline, human, rhesus macaque,
and porcine TNF-alpha. It 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 (13). Cell surface
TNF-alpha can both induce the lysis of
tumor cells and virus infected cells, and generate its own
downstream cell signaling following
ligation by soluble TNF RI (14, 15). Shedding of membrane
bound TNF-alpha by TACE/ADAM17
releases the bioactive cytokine, a 55 kDa soluble trimer of
the TNF-alpha extracellular domain
(16-18).
TNF-alpha binds the ubiquitous 55 - 60 kDa TNF RI (19, 20) and
the hematopoietic cell-restricted
78-80 kDa TNF RII (21, 22), both of which are also expressed
as homotrimers (1, 23). Both type I
and type II receptors bind TNF-alpha with comparable affinity
and can promote NF kappa B activation
(24-27). Only TNF RI, however, contains a cytoplasmic death
domain which triggers the
activation of apoptosis (3, 28). Soluble forms of both types
of receptors are released into
human serum and urine and can neutralize the biological
activity of TNF-alpha (29-31).
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