Tumor necrosis factor (TNF) was originally identified as an endogenous mediator of hemorrhagic necrosis of experimental tumors in rabbits. This hemorrhagic necrosis is caused by bacterial products, especially lipopolysaccharide derived from the walls of gram-negative bacteria (1,2). Human TNF protein was purified to homogeneity, and its complete amino acid sequence was determined (3,4); a complementary DNA (cDNA) was subsequently cloned and expressed (4). At the time of cloning, the molecule was renamed as TNF-α to emphasize its close structural relationship to lymphotoxin (LT)-α, then designated as TNF-β. (This latter name has gone out of use, so the names TNF and TNF-α are now synonymous, and the designation “α” is superfluous.) Cachectin was independently identified as a mediator of inflammation and as a mediator of cachexia in parasitic infections (2). Following its purification, amino acid sequencing established murine cachectin as identical to TNF (5).

TUMOR NECROSIS FACTOR FAMILY

TNF and LT-α define the TNF superfamily of secreted and cell-surface proteins that bind to structurally related receptors (the TNFR superfamily) (6). The TNF superfamily is largely confined to vertebrates and probably coevolved with the adaptive immune system, although a single TNF-like molecule recently has been identified in Drosophila (6). The largest cluster of TNF superfamily molecules, including both TNF and LT-α, is encoded within the major histocompatibility complex. Knockout of TNF gene in mice leads to abnormal formation of Peyer's patches in the small intestine but otherwise normal development (7).

The primary cellular sources of TNF are leukocytes, especially mononuclear phagocytes, T lymphocytes, and mast cells (8).