Immunity and inflammation

At low concentrations, TNF-a activates a range of leukocytes that mediate selected elements of both specific and non-specific immunity. These TNF-a actions include:

• activation of various phagocytic cells, including macrophages, neutrophils and polymorphonu-clear leukocytes;

• enhanced toxicity of eosinophils and macrophages towards pathogens;

• exerting antiviral activity somewhat similar to class I interferons, and increasing surface expression of class I MHC molecules on sensitive cells;

• enhancing proliferation of IL-2-dependent T-lymphocytes.

In addition, TNF-a influences immunity indirectly by promoting synthesis and release of a variety of additional cytokines, including interferons, IL-1, IL-6, IL-8 and some CSFs.

TNF-a also plays a prominent role in mediating the inflammatory response; indeed, this may be its major normal physiological role. It promotes inflammation by a number of means, including:

• Promoting activation of neutrophils, eosinophils and other inflammatory leukocytes.

• Induction of expression of various adhesion molecules on the surface of vascular endothelial cells. These act as docking sites for neutrophils, monocytes and lymphocytes, facilitating their accumulation at local sites of inflammation.

• Displays chemotactic effects, especially for monocytes and polymorphonuclear leukocytes.

• Enhances vascular leakness by promoting a reorganization of the cytoskeleton of endothelial cells.

• Induction of synthesis of various lipid-based inflammatory mediators, including some prostaglandins and platelet-activating factor, by macrophages and other cells. Many of these promote sustained vasodilation and increased vascular leakage.

• Induction of synthesis of pro-inflammatory cytokines, such as IL-1 and IL-8.

TNF-a, therefore, promotes various aspects of immunity and inflammation. Blockage of its activity, e.g. by administration of anti-TNF-a antibodies, has been shown to compromise the body's ability to contain and destroy pathogens.

TNF-a exhibits cytotoxic effects on a wide range of transformed cells. Indeed, initial interest in this molecule (and its naming) stems from its anti-tumour activity. These investigations date back to the turn of the century, when an American doctor, William Coley, noted that tumours regressed in some cancer patients after the patient had suffered a severe bacterial infection. Although such observations prompted pioneering scientists to treat some cancer patients by injection with live bacteria, the approach was soon abandoned because many patients died due to the resulting uncontrolled bacterial infections, before they could be 'cured' of the cancer. The active tumour agent turned out to be TNF-a (high circulating levels of which were induced by the bacterially derived LPS).

TNF fails to induce death of all tumour cell types. Although many transformed cells are TNF sensitive, the cytokine exerts, at best, a cytostatic effect on others and has no effect on yet others. The cytotoxic activity is invariably enhanced by the presence of IFN-y. The concurrent presence of this interferon increases the range of transformed cell types sensitive to TNF-a, and can upgrade its cytostatic effects to cytotoxic effects. It can also render many untransformed cells, in particular epithelial and endothelial cells, susceptible to the cytotoxic effects of TNF-a.

TNF-a can mediate death of sensitive cells via apoptosis or necrosis (necrotic death is characterized by clumping of the nuclear chromatin, cellular swelling, disintegration of intracellular organelles and cell lysis; apoptotic death is characterized by cellular shrinking, formation of dense 'apoptotic' masses and DNA fragmentation).

In addition to its cytotoxic effects, TNF-a appears to regulate the growth of some (non-transformed) cell types. It is capable of stimulating the growth of macrophages and fibroblasts, while suppressing division of haematopoietic stem cells. The systemic effects of this cytokine on cellular growth in vitro are thus complex and, as yet, only poorly appreciated.

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