Tumor Necrosis Factor

Tumor necrosis factor (TNF) is a mediator of the acute inflammatory response to bacteria and other infectious microbes. The name of this cytokine derives from its original identification as a serum substance (factor) that caused necrosis of tumors, now known to be the result of local inflammation and thrombosis of tumor blood vessels. TNF is also called TNF-a to distinguish it from the closely related TNF-ß, also called lymphotoxin. TNF is produced by macrophages, dendritic cells, and other cell types. In macrophages, it is synthesized as a nongly-cosylated type II membrane protein and is expressed as a homotrimer, which is able to bind to one form of TNF receptor. The membrane form of TNF is cleaved by a membrane-associated metalloproteinase, releasing a polypeptide fragment, and three of these polypeptide chains polymerize to form a triangular pyramid-shaped circulating TNF protein (Fig. 4-11). The receptor-binding sites are at the base of the pyramid, allowing simultaneous binding of the cytokine to three receptor molecules.

There are two distinct TNF receptors called type I (TNF-RI) and type II (TNF-RII). The affinities of TNF for its receptors are unusually low for a cytokine, the Kd being only ~1 x 10-9 M for binding to TNF-RI and approximately 5 x 10-10 M for binding to TNF-RII. Both TNF receptors are present on most cell types. The TNF receptors are members of a large family of proteins called the TNF receptor superfamily, many of which are involved

FIGURE 4-11 Structure of the TNF receptor with bound lymphotoxin. The ribbon structure depicts a top view of a complex of three TNF receptors (TNF-RI) and one molecule of the bound cytokine, revealed by x-ray crystallography. Lymphotoxin is a homotrimer in which the three subunits are colored dark blue. The lymphotoxin homotrimer forms an inverted three-sided pyramid with its base at the top and its apex at the bottom. Three TNF-RI molecules, colored magenta, cyan, and red, bind one homotrimer of lymphotoxin, with each receptor molecule interacting with two different lymphotoxin monomers in the homotrimer complex. Disulfide bonds in the receptor are colored yellow. TNF is homologous to lymphotoxin and presumably binds to its receptors in the same way. (From Banner DW, et al, Cell: Crystal structure of the soluble human 55 kd TNF receptor-human TNFfi complex: 73:431-445. © Cell Press, 1993).

FIGURE 4-11 Structure of the TNF receptor with bound lymphotoxin. The ribbon structure depicts a top view of a complex of three TNF receptors (TNF-RI) and one molecule of the bound cytokine, revealed by x-ray crystallography. Lymphotoxin is a homotrimer in which the three subunits are colored dark blue. The lymphotoxin homotrimer forms an inverted three-sided pyramid with its base at the top and its apex at the bottom. Three TNF-RI molecules, colored magenta, cyan, and red, bind one homotrimer of lymphotoxin, with each receptor molecule interacting with two different lymphotoxin monomers in the homotrimer complex. Disulfide bonds in the receptor are colored yellow. TNF is homologous to lymphotoxin and presumably binds to its receptors in the same way. (From Banner DW, et al, Cell: Crystal structure of the soluble human 55 kd TNF receptor-human TNFfi complex: 73:431-445. © Cell Press, 1993).

in immune and inflammatory responses. These receptors exist as trimers in the plasma membrane. Cytokine binding to some TNF receptor family members, such as TNF-RI, TNF-RII, and CD40, leads to the recruitment of proteins, called TNF receptor-associated factors (TRAFs), to the cytoplasmic domains of the receptors. The TRAFs activate transcription factors, notably NF-kB and AP-1. Cytokine binding to other family members, such as TNF-RI, leads to recruitment of an adaptor protein that activates caspases and triggers apoptosis. Thus, different members of the TNF receptor family can induce gene expression or cell death, and some can do both (see Chapter 7).

TNF production by macrophages is stimulated by PAMPs and DAMPs. TLRs, NLRs, and RLRs can all induce TNF gene expression, in part by activation of the NF-kB transcription factor. Many different microbial products can therefore induce TNF production. Large amounts of this cytokine may be produced during infections with gram-negative and gram-positive bacteria, which release the TLR ligands LPS and lipoteichoic acid, respectively, from their cell walls. Septic shock, a life-threatening condition caused when bacteria enter the blood stream, is mediated in large part by TNF. We will discuss septic shock later in this chapter.

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