Mouse 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 179 aa
extracellular domain (ECD) (12). Within the ECD, mouse TNF-alpha
shares 95% aa identity with rat,
and 80% aa identity with canine, equine, feline, human,
rabbit, 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 containing 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 NFkB 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 (29-31).
Powered by Bioz
