TNF biochemistry

TNF-a is also known as cachectin, macrophage cytotoxic factor, macrophage cytotoxin and necrosin. As some of these names suggest, activated macrophages appear to represent the most significant cellular source of TNF-a, but it is also synthesized by many other cell types (Table 5.9). Producer cells do not store TNF-a, but synthesize it de novo following activation. 

Human TNF-a is initially synthesized as a 233 amino acid polypeptide, which is anchored in the plasma membrane by a single membrane-spanning sequence. This TNF pro-peptide, which itself displays biological activity, is usually proteolytically processed by a specific extracellular metalloprotease. Proteolytic cleavage occurs between residues 76 (Ala) and 77 (Val), yielding the mature (soluble) 157 amino acid TNF-a polypeptide. Mature human TNF-a appears to be devoid of a carbohydrate component and contains a single disulphide bond. 

A number of stimuli are known to act as inducers of TNF production (Table 5.10). Bacterial lipopolysaccharide represents the most important inducer, and TNF mediates the pathophysiological effects of this molecule. TNF biosynthesis is regulated by both transcriptional and post-transcriptional mechanisms. Macrophages appear to constitutively express TNF-a mRNA, 

B and T l5unphoc5des Pol5unorphonuclear leukocytes Astrocytes Langerhans cells Brain microglial cells Various transformed cell lines 

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