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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