Tumor Necrosis Factor Tnf Receptor Proteins

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 Tumor Necrosis Factor Tnf Receptor Proteins Background

Tumor necrosis factor (TNF) is a pleiotropic cytokine that regulates a wide spectrum of biological processes including inflammation, innate and adaptive immune response, cell proliferation, differentiation, apoptosis, and lipid metabolism. TNF is produced primarily by macrophages and monocytes, but it is produced also by a broad variety of cell types including lymphoid cells, mast cells, endothelial cells and fibroblasts. Large amounts of TNF are released in response to lipopolysaccharide, other bacterial products, and IL-1. 
Although inflammatory and immunomodulatory activities of TNF attracted the greatest research interest so far, it was originally identified as a protein that kills tumor cells. In 1975 a paper entitled "An endotoxin-induced serum factor that causes necrosis of tumors" reported a cytotoxic factor produced by macrophages, and named it TNF. Around the same time, Granger and co-workers described another protein produced by lymphocytes that was toxic to tumor cells and named it lymphotoxin (LT). When the cDNAs encoding LT and TNF were cloned in 1984-1985, they 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 and LT as TNFβ. 
Research during the past two decades has shown the existence of a superfamily of TNF proteins consisting of 19 members that signal through 29 receptors with a wide range of roles beyond cytotoxicity, being involved in the development and function of the immune system as well as in tissue homeostasis. The members of the TNF superfamily exhibit 15-25% amino acid sequence homology with each other and bind to distinct receptors, which are homologous in their extracellular domain. The cytokines belonging to TNF family includes TNFα, TNFβ, BAFF, RANKL, APRIL, TRAIL, FasL, etc. Members of the TNF receptor superfamily play pivotal roles in numerous biological events in metazoan organisms. However, within this gene family, TNF (also known as TNFα) was recognized as a uniquely powerful intercellular communicating molecule with crucial and non-redundant roles in innate and adaptive immunity.
TNF exists as a membrane-anchored and soluble form, both of which show biological activity. 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 TNFα converting enzyme (TACE, also called ADAM17). 
Response to TNF is mediated through two receptors, TNF-R1, which is widely expressed, and TNF-R2, which is expressed mainly in immune and endothelial cells. These two receptors for TNF, TNF-R1 (55 kDa) and TNF-R2 (75 kDa) can mediate distinct cellular responses. Most information regarding TNF signaling is derived from TNF-R1, although both receptors have been characterized which can bind TNF and may play an important role in immune disorders. Upon contact with their ligand, TNF receptors 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 active downstream signaling of TRADD. TRADD recruits TRAF2 and RIP. TRAF2 in turn recruits the multicomponent protein kinase IKK, enabling the serine-threonine kinase RIP to activate it. An inhibitory protein, IKBCX, 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 responses, and antiapoptotic factors. TNF also induces a strong activation of the stress-related JNK group, evokes moderate response of the p38-MAPK, and is responsible for minimal activation of the classical ERKs. JNK translocates to the nucleus and activates transcription factors such as c-Jun and ATF2. The JNK pathway is involved in cell differentiation, proliferation, and is generally pro-apoptotic. 
Like all death-domain-containing members of the TNFR superfamily, TNF-R1 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 is often masked by the anti-apoptotic effects of NF-κB. Nevertheless, TRADD binds FADD, which then recruits the cysteine protease caspase-8. A high concentration of caspase-8 induces its autoproteolytic activation and subsequent cleavage of effector caspases, leading to cell apoptosis.
TNF is one of the most prominent inflammatory mediators and absolutely central in initiating the inflammatory reactions of the innate immune system, including induction of cytokine production, activation and expression of adhesion molecules, and growth stimulation. TNF promotes the production of more cytokines including IL-1, and enhances the stimulation of T and B cells and other immune system cells to make a response to antigenic challenge more potent. By the use of gene-targeted mice it has been shown that deletion of either TNF or TNF-R1 leads to highly increased susceptibility to challenge with infectious agents. TNF or TNF-R1 KO mice succumb to infection with Listeria monocytogenes, resulting in rapid death from infection. They also have a deficiency in granuloma development and do not form germinal centers after immunization, indicating a crucial role of TNF in immunity. 
However, these properties of TNF can also be a disadvantage too. TNF has been implicated in a variety of diseases, including sepsis, autoimmune diseases, insulin resistance and cancer, when its action is not carefully controlled. In 1985, Beutler et al. discovered that TNF is a mediator of lethal endotoxin toxicity. Mice deficient in TNF or TNF-R1 are resistant to the lethality induced by LPS under conditions where hepatic RNA and, ultimately, protein synthesis, is inhibited by D-galactosamine. In autoimmune diseases such as RA, several studies originally demonstrated by Kollias and colleagues using hTNF transgenic animal models indicated that hTNF transgenic mice developed an erosive arthritis with similar histological characteristics to RA, confirming the physiological role of TNF in the development of arthritis. Significance of TNF in mediating the arthritogenic response has been demonstrated by the amelioration of arthritic lesions in anti-TNF-treated animal models of arthritis and most importantly in human disease.