Tumour necrosis factor 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 9.5). 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 that 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 metallo-protease. 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 disulfide bond.

Monomeric TNF is biologically inactive; the active form is a homotrimer in which the three monomers associate non-covalently about a threefold axis of symmetry, forming a compact bell-shaped structure. X-ray crystallographic studies reveal that each monomer is elongated and characterized by a large content of antiparallel P pleated sheet, which closely resembles subunit proteins of many viral caspids (Figure 9.4).

A number of stimuli are known to act as inducers of TNF production (Table 9.6). Bacterial LPS 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 express TNF-a mRNA constitutively, which is translated only

Table 9.5 The major cellular sources of human TNF-p. As is evident, TNF-a synthesis is not restricted to cells of the immune system, but is undertaken by a wide variety of different cells in different anatomical locations, including the brain

Macrophages

NK cells

Eosinophils

Hepatic Kupffer cells

Glomerular mesangial cells

Fibroblasts

B- and T-lymphocytes Polymorphonuclear leukocytes Astrocytes Langerhan's cells Brain microglial cells Various transformed cell lines

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Figure 9.4 Three-dimensional structure of TNF-a. Structural details courtesy of the Protein Data Bank, http ://www.rcsb.org/pdb/

upon their activation. After activation, the rate of gene expression may increase only threefold, although cellular TNF-a mRNA levels may increase 100-fold and secretion of soluble TNF-a may increase 10 000-fold.

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