Tumor Necrosis Factor a

Lothar Rink, Institute of Immunology and Transfusion Medicine, University of Lübeck School of Medicine, Lübeck, Germany

The remission of tumors after bacterial infections was first described in 1866. In 1893 Coley described tumor necrosis after treatment of patients with bacterial toxins from Streptococcus and Serratia, which were later named 'Coley's toxin'. Over 100 years after the first clinical observation, tumor necrosis factor a (TNFa) was described in 1975 by Carswell and colleagues. They reported on a soluble factor in the serum of endotoxin-treated bacillus Calmette-Guerin (BCG)-infected mice, which causes hemorrhagic necrosis of tumors.

TNFa has had a number of synonyms (Table 1). It is induced by all types of microorganisms and a number of their products (Table 2). The expression of TNFa has naturally counteracting cytokines (Table 2). Nearly all cell types are able to produce TNFa (Table 3) and respond to TNFa treatment

Table 1 Synonyms for TNFa

Cachectin Cytotoxin (CTX)

Differentiation-inducing factor (DIF)

Endogenous pyrogen (EP) (also synonym for interleukin 1)

Hemorrhagic factor

Macrophage cytotoxic factor (MCF)

Macrophage cytotoxin (MCT)

Necrosin

Tumor necrosis factor (TNF)

(Table 4). Over all the biological effects, the cytotoxic effects of TNFa and its induction of apoptosis seem to be the most important.

Table 2 Inducers and suppressors of TNFa production

Inducer

Allogenic cells Bacteria

Bacterial cell walls Complement

Cytokines (i.e. IL-1, GM-CSF) Immune complexes Lipid A

Lipopolysaccharide (LPS) Lipoteichoic acid Mycoplasma membrane Mycoplasma components Parasites Peptidoglycan Phorbol esters Reactive oxygen species Superantigens Tumor cells Viruses Yeast Zinc ions Zymosan

Suppressor

Cyclosporine Glucocorticoids (i.e. dexamethasone)

Interleukin 4 Interleukin 10 Interleukin 13 Lipo-oxygenase inhibitors Metalloproteinase inhibitors (only for soluble TNF) Phosphodiesterase inhibitors Transforming growth factor ß

Table 3 TNFa-producing cells Adipocytes

Antigen-presenting cells

Astrocytes

B cells

Breast cells

Epidermal cells

Fibroblasts

Glial tumor cells

Granulocytes

Macrophages

Mast cells

Monocytes

Neutrophils ?

NK cells

Smooth muscle cells Synoviocytes T cells

Table 4 Biological effects of TNFa

Antiviral activity Chemotactic

Decreased lipoprotein lipase synthesis

Differentiation of monocytes

Enhanced antibody-dependent cellular cytotoxicity

Increased expression of adhesion molecules

Increased MHC class I and class II expression

Increased phagocytotic activity

Increased proliferation of fibroblasts

Induced adhesion to endothelium

Induced degranulation

Induced fever

Induced hypotension

Induction of apoptosis

Induction of granulocyte/macrophage-colony stimulating factor

Induction of interleukin 1 and 6 Induction of procoagulant activity Induction of reactive oxygen species Influence on hematopoiesis of myeloid cells Inhibition of intracellular parasites and bacteria Regulation of acute phase proteins Regulation of extracellular matrix formation Regulation of proliferation of T and B cells Regulation of T and B cell functions

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