Human 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 177 aa
extracellular domain (ECD) (12, 13). Within the ECD, human TNF-alpha shares 97% aa sequence
identity with rhesus monkey, and 71%-92% aa identity with bovine, canine, cotton rat, equine,
feline, mouse, porcine, and rat 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 (14). 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 (15, 16). Shedding of membrane bound TNF-alpha by TACE/
ADAM17 releases the bioactive cytokine, a 55 kDa soluble trimer of the TNF-alpha extracellular
domain (17-19).
TNF-alpha binds the ubiquitous 55-60 kDa TNF RI (20, 21) and the hematopoietic cell-restricted
78-80 kDa TNF RII (22, 23), both of which are also expressed as homotrimers (1, 24). Both
type I and type II receptors bind TNF-alpha with comparable affinity and can promote NF kappa B
activation (25-28). Only TNF RI, however, contains a cytoplasmic death domain which triggers
the activation of apoptosis (3, 29). Soluble forms of both types of receptors are released into
human serum and urine and can neutralize the biological activity of TNF-alpha (30-32).
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