Natural production and release of tumour necrosis factor

Tumour necrosis factor (TNF) was first described as an oncolytic factor found in sera of animals injected (primed) with reticuloendothelial stimulators and subsequently (days later) given lipopolysaccharide (LPS). TNF is not found in the serum of 'primed' animals but can be found in animals given LPS alone when sensitive assays are employed. TNF appears almost immediately upon LPS injection, reaches a maximum from about 1.5-2 hours and disappears rapidly thereafter, and is almost undetectable by 4-6 hours. When such mice are injected again with LPS, they are unresponsive (tolerized) and do not produce TNF again, at least for seven days. Other unrelated substances, such as muramyl dipeptide, viruses and mitogens, also induce TNF production. A high percentage of patients with some parasitic infections (but not cancers) demonstrate low levels of TNF in their sera; thus, they do not seem to be tolerized but produce it continuously. TNF can also be produced in macrophage cultures by treatment with LPS, muramyl dipeptide and other substances. Again, it appears almost immediately and synthesis is maintained for about 8-12 hours. Synthesis is dependent upon the continuous presence of LPS. After synthesis stops it cannot be reinitiated by adding more LPS; thus, the macrophages also appear to be tolerized. Macrophage cell lines eventually become sensitive again after cultivation in LPS-free conditions. Synthesis of TNF is inhibited by actinomycin D or cycloheximide, indicating that it is an inducible protein. Its production is also inhibited by glucocorticoids and prostaglandin E2, indicating that these substances play important roles in the regulation of TNF synthesis.