Biological activities of tumour necrosis factora

The availability of large quantities of recombinant TNF-a facilitates rigorous investigation of the effects of this cytokine on cells in vitro, as well as its systemic in vivo effects. Like most cytokines, TNF-a exhibits pleiotropic effects on various cell types. The major biological responses induced by this cytokine include:

• activation of certain elements of both non-specific and specific immunity, in particular in response to Gram-negative bacteria;

Table 9.6 Major physiological inducers of TNF-a production

LPS Bacterial enterotoxin

Mycobacteria Various viruses

Fungi Parasites

Antibody-antigen complexes Various cytokines (e.g. IL-1)

Inflammatory mediators TNF-a (autocrine activity)

• induction/regulation of inflammation;

• selective cytotoxic activity against a range of tumour cells;

• mediation of various pathological conditions, including septic shock, cachexia and anorexia.

The exact range of biological effects induced by TNF-a is dependent upon a number of factors, most notably the level at which TNF-a is produced. At low concentrations, TNF-a acts locally in a paracrine and autocrine manner, predominantly influencing white blood cells and endothelial cells. Under such circumstances, TNF-a's major activity relates to regulation of immunity and inflammation. In some situations, however, very large quantities of TNF-a may be produced (e.g. during severe Gram-negative bacterial infections). In such instances, TNF-a enters the blood stream and acts in an endocrine manner. Systemic effects of TNF-a (systemic means relating to the whole body, not just a specific area or organ), which include severe shock, are largely detrimental. Prolonged elevated systemic levels of TNF-a induce additional effects on, for example, whole-body metabolism. Many of TNF-a's biological effects are augmented by interferon-y

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