Tumour Necrosis Factors

The cytokine tumour necrosis factor is a major mediator of natural immunity and is a potent stimulus for many inflammatory and immune functions of the body.

Keywords: TNF; cytokine; inflammation; lymphotoxin; apoptosis

Figure 1. Space-filling model of the homotrimeric tumour necrosis factor (TNF). The separate subunits are depicted in blue, light red and brown. Additionally, the marked spheres belong to the side-chain atoms of amino acids which are critical for TNF-receptor binding in the binding cleft which is formed by two of the three subunits: the residues shown in red (Arg32) and light blue (Ser86) are essential for binding to TNF-R2, whereas the residues shown in yellow (Asp143) and green (Ala145) are essential for binding to TNF-R1. The upper image shows the top-view of the molecule (facing towards the N- and C-termini) and the lower image is flipped by 90° along the horizontal axis.
Figure 2. Biological activities of tumour necrosis factor (TNF) on different cells and tissues. Almost all nucleated cell types in the body express TNF receptors and are thus potentially reactive to TNF. Among the countless effects described for TNF, the most important is its role as a central regulator of inflammation and immunity. Monocytes and macrophages are the main producers of TNF, although numerous cell types can express TNF in response to diverse stimuli. IL, interleukin; IFN, interferon; GM-CSF, granulocyte–macrophage colony-stimulating factor; PGE, prostaglandin E; MHC, major histocompatibility complex.
Figure 3. Schematic representation of the major receptor-proximal signalling pathways induced by tumour necrosis factor (TNF). The cellular mechanisms of TNF signalling are an area of intense research and the presented scheme therefore covers the best-described signalling pathways of TNF only. Upon binding of TNF (shown in dark green) to TNF-R1 (extracellular four cysteine-rich domains (blue colour) and intracellular death domain (orange colour) an initial protein complex (complex I) is formed at the plasma membrane leading to the activation of diverse MAPKKKs (ASK1, MEKK1, TAK1, MEKK3; for details see text). Further dowstream kinases of the MAPK cascade become activated, finally resulting in the activation of transcription factors (c-Jun, ATF2, CHOB). In addition, the activation of the IKK complex (‘signalosome’) leads to the liberation of the transcription factor NF-B that translocates into the nucleus to induce gene transcription of several antiapoptotic, proliferative and inflammatory genes (e.g. IAPs, cyclines, interleukins). Signalling pathways requiring TRAF2 are indicated by red arrows, those dependent on RIP1 are shown in blue arrows. The formation of the secondary complex (complex II) is shown by the sequential clustering (1) and internalization (2) of TNF-R1. The formation of complex II leads to the recruitment of other proteins, such as FADD and caspase 8/10. Effector caspases can be activated by two pathways, either directly by active caspase 8/10 or indirectly by the mitochondrion. The mitochondrial pathway can be initiated by proteolytically processed forms of the proapoptotic Bcl-2 family member Bid (tBid and jBid). The subsequent release of the mitochondrial proapoptotic factor second mitochondria-derived activator of caspase (Smac, also known as DIABLO) counteracts caspase inhibitors from the IAP family. Likewise, released cytochrome c leads to the formation of a multi-protein complex called the ‘apoptosome’. Finally, effector caspases accomplish the destruction of the cell. The exact composition of complexes I/II is not yet defined (marked with a (?)). For more details see text.
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 Further Reading
    Chang L, Kamata H, Solinas G et al. (2006) The E3 ubiquitin ligase itch couples JNK activation to TNF-induced cell death by inducing c-FLIP(L) turnover. Cell 124: 601–613.
    Ea CK, Deng L, Xia ZP, Pineda G and Chen ZJ (2006) Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Molecular Cell 22: 245–257.
    Friedmann E, Hauben E, Maylandt K et al. (2006) SPPL2a and SPPL2b promote intramembrane proteolysis of TNF in activated dendritic cells to trigger IL-12 production. Nature Cell Biology 8: 843–848.
    Heinrich M, Neumeyer J, Jakob M et al. (2004) Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death and Differentiation 11: 550–563.
    Sato S, Sanjo H, Takeda K et al. (2005) Essential function for the kinase TAK1 in innate and adaptive immune responses. Nature Immunology 6: 1087–1095.
    Sebban H, Yamaoka S and Courtois G (2006) Posttranslational modifications of NEMO and its partners in NF-B signaling. Trends in Cellular Biology 16: 569–577.
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Branschädel, Marcus, Boschert, Verena, and Krippner‐Heidenreich, Anja(Sep 2007) Tumour Necrosis Factors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000935.pub2]