Tumor Necrosis Factors (TNF) and Related Peptides

Definition
Tumour necrosis factors (TNF), TNF-a and TNF-ß (previously called lymphotoxin), are the products of activated monocytes and lymphocytes, respectively, and both have recently been purified, sequenced and cloned by recombinant DNA methods, revealing 35% identity and 50% homology in the amino-acid sequence 1.

Related Peptides
Human TNF and Lymphotoxin are cytotoxic proteins which have similar biological activities and share 30 % amino acid homology. The single copy genes which encode these proteins share several structural features: each gene is approximately 3kb pairs in length and is interrupted by three introns. In addition, these genes are closely linked and have been mapped to human chromosome 6. However, only the last exons of both genes, which code for more than 80 percent of each secreted protein, are significantly homologous (56 %) 2.

Discovery
TNF was first described by Carswell et al., in 1975, as a factor present in infected, endotoxin-injected mice that caused hemorrhagic necrosis of transplanted sarcomas 3.

Structural Characteristics
TNF is initially synthesized as a biologically active, 26-kDa type-II transmembrane proform consisting of a presequence, which functions as a membrane anchor, and the extracellular 17-kDa TNF. Trimerization occurs already at the proform stage and the 26-kDa proform subunits are then cleaved proteolytically at the cell surface by TNF convertase, releasing mature, trimeric TNF4.

Mode of Action
TNF-a is a potent proinflammatory cytokine that plays an important role in immunity and inflammation, and in the control of cell proliferation, differentiation and apoptosis. TNF-a is also the founding member of a still growing family of cytokines with diverse bioregulatory functions. Considerable progress has been made in understanding the molecular mechanisms that mediate TNF-a-induced cellular responses. Binding of TNF-a to its two receptors, TNFR1 and TNFR2, results in recruitment of signal transducers that activate at least three distinct effectors. Through complex signaling cascades and networks, these effectors lead to the activation of caspases and two transcription factors, AP-1 and NF-kappaB. Similar signaling mechanisms are likely to be used by other members of the TNF family 5.

Functions
TNF-a is a highly potent proinflammatory cytokine with a wide range of activities in both inflammatory and immune responses. TNF and the related cytokine lymphotoxin-a (LT-a) are essential for host resistance against infection with Mycobacterium tuberculosis and other mycobacteria. The importance of TNF-dependent granuloma formation in the control of latent M. tuberculosis infection in humans is graphically illustrated by the rapid reactivation of clinical tuberculosis in patients undergoing treatment for rheumatoid arthritis and Crohn’s disease with a humanized mAb to TNF 6.

References
1. Aggarwal BB, Eessalu TE, Hass PE (1985). Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon. Nature, 318(6047):665-667.
2. Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW (1985). Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res., 13(17):6361-6373.
3. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975). An endotoxin-induced serum factor that causes necrosis of tumors. PNAS., 72:3666-3670.
4. Decoster E, Cornelis S, Vanhaesebroeck B, Fiers W (1998). Autocrine tumor necrosis factor (TNF) and lymphotoxin (LT) a differentially modulate cellular sensitivity to tnf/lt-a cytotoxicity in l929 cells. J Cell Biol.,143(7):2057-2065.
5. Baud V, Karin M (2001). Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol., 11(9):372-377.
6. Roach DR, Bean AGF, Demangel C, France MP Briscoe H, Britton WJ (2002). TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. The Journal of Immunology, 168:4620-4627.

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