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. 

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 

B- and T-lymphocytes Polymorphonuclear leukocytes Astrocytes Langerhan s cells Brain microglial cells Various transformed cell lines 

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The dream of Stewart Adams, to find not only a palliative treatment but also a cure for rheumatoid diseases, did unfortunately not come true. [180] Pro-inflammatory cytokines like interleukin-1 and -6, or the tumour-necrosis factor-a (TNF-a) play key roles in diseases of the rheumatoid spectrum, and impact a multitude of signalling cascades within the immune system. Accumulating insight into the pathophysiology, biochemistry, cellular and molecular biology of these illnesses has clearly improved the opportunities for their treatment at the... 

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