Tumor necrosis factor (TNF, cachexin, or cachectin, and formerly known as tumor necrosis factor alpha or TNFα) is an adipokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction. It is produced chiefly by activated macrophages (M1), although it can be produced by many other cell types such as CD4+ lymphocytes, NK cells and neurons.
The cDNAs encoding LT and TNF were cloned in 1984 and were revealed to be similar. The binding of TNF to its receptor and its displacement by LT confirmed the functional homology between the two factors. The sequential and functional homology of TNF and LT led to the renaming of TNF as TNFα (this article) and LT as TNFβ. In 1985, Bruce A. Beutler and Anthony Cerami discovered that cachectin (a hormone which induces cachexia) was actually TNF. They then identified TNF as a mediator of lethal endotoxin poisoning.Kevin J. Tracey and Cerami discovered the key mediator role of TNF in lethal septic shock, and identified the therapeutic effects of monoclonal anti-TNF antibodies. More recently, research in the Laboratory of Mark Mattson has shown that TNF can prevent the death/apoptosis of neurons by a mechanism involving activation of the transcription factor NF-kappaB which induces the expression of Mn-SOD and Bcl-2.
TNF is primarily produced as a 212-amino acid-long type II transmembrane protein arranged in stable homotrimers. From this membrane-integrated form the soluble homotrimeric cytokine (sTNF) is released via proteolytic cleavage by the metalloprotease TNF alpha converting enzyme (TACE, also called ADAM17). The soluble 51 kDa trimeric sTNF tends to dissociate at concentrations below the nanomolar range, thereby losing its bioactivity. The secreted form of human TNFα takes on a triangular pyramid shape, and weighs around 17-kD. Both the secreted and the membrane bound forms are biologically active, although the specific functions of each is controversial. But, both forms do have overlapping and distinct biology activities.
TNF can bind two receptors, TNFR1 (TNF receptor type 1; CD120a; p55/60) and TNFR2 (TNF receptor type 2; CD120b; p75/80). TNFR1 is expressed in most tissues, and can be fully activated by both the membrane-bound and soluble trimeric forms of TNF, whereas TNFR2 is found only in cells of the immune system, and respond to the membrane-bound form of the TNF homotrimer. As most information regarding TNF signaling is derived from TNFR1, the role of TNFR2 is likely underestimated.
Signaling pathway of TNFR1. Dashed grey lines represent multiple steps.
Upon contact with their ligand, TNF receptors also form trimers, their tips fitting into the grooves formed between TNF monomers. This binding causes a conformational change to occur in the receptor, leading to the dissociation of the inhibitory protein SODD from the intracellular death domain. This dissociation enables the adaptor proteinTRADD to bind to the death domain, serving as a platform for subsequent protein binding. Following TRADD binding, three pathways can be initiated.
Activation of NF-κB: TRADD recruits TRAF2 and RIP. TRAF2 in turn recruits the multicomponent protein kinaseIKK, enabling the serine-threonine kinase RIP to activate it. An inhibitory protein, IκBα, that normally binds to NF-κB and inhibits its translocation, is phosphorylated by IKK and subsequently degraded, releasing NF-κB. NF-κB is a heterodimeric transcription factor that translocates to the nucleus and mediates the transcription of a vast array of proteins involved in cell survival and proliferation, inflammatory response, and anti-apoptotic factors.
Induction of death signaling: Like all death-domain-containing members of the TNFR superfamily, TNFR1 is involved in death signaling. However, TNF-induced cell death plays only a minor role compared to its overwhelming functions in the inflammatory process. Its death-inducing capability is weak compared to other family members (such as Fas), and often masked by the anti-apoptotic effects of NF-κB. Nevertheless, TRADD binds FADD, which then recruits the cysteine proteasecaspase-8. A high concentration of caspase-8 induces its autoproteolytic activation and subsequent cleaving of effector caspases, leading to cell apoptosis.
The myriad and often-conflicting effects mediated by the above pathways indicate the existence of extensive cross-talk. For instance, NF-κB enhances the transcription of C-FLIP, Bcl-2, and cIAP1 / cIAP2, inhibitory proteins that interfere with death signaling. On the other hand, activated caspases cleave several components of the NF-κB pathway, including RIP, IKK, and the subunits of NF-κB itself. Other factors, such as cell type, concurrent stimulation of other cytokines, or the amount of reactive oxygen species (ROS) can shift the balance in favor of one pathway or another. Such complicated signaling ensures that, whenever TNF is released, various cells with vastly diverse functions and conditions can all respond appropriately to inflammation.
On other tissues: increasing insulin resistance. This mechanism occurs as TNF phosphorylates serine residues on the insulin receptor causing signal to stop at the cell surface.
A local increase in concentration of TNF will cause the cardinal signs of Inflammation to occur: heat, swelling, redness, pain and loss of function.
Whereas high concentrations of TNF induce shock-like symptoms, the prolonged exposure to low concentrations of TNF can result in cachexia, a wasting syndrome. This can be found, for example, in cancer patients.
Said et al. showed that TNFα causes an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.
Recent research by Pedersen et al. indicates that TNFα increase in response to sepsis is inhibited by the exercise-induced production of myokines. To study whether acute exercise induces a true anti-inflammatory response, a model of ‘low grade inflammation’ was established in which a low dose of E. coli endotoxin was administered to healthy volunteers, who had been randomised to either rest or exercise prior to endotoxin administration. In resting subjects, endotoxin induced a 2- to 3-fold increase in circulating levels of TNFα. In contrast, when the subjects performed 3 hours of ergometer cycling and received the endotoxin bolus at 2.5 h, the TNFα response was totally blunted. This study provides some evidence that acute exercise may inhibit TNF production.
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