TNF receptor

Both receptor types are members of the nerve growth factor receptor superfamily and exhibit the characteristic four (cysteine-rich) repeat units in their extracellular domain. The extracellular domains of TNF-R55 and TNF-R75 exhibit only 28% homology while their intracellular domains are devoid of any homology, indicating the likely existence of distinct signalling mechanisms. 

It appears that TNF-R55 is capable of mediating most TNF activities, while the biological activities induced via the TNF-R75 receptor are more limited. For example, TNF s cytotoxic activity, as well as its ability to induce synthesis of various cytokines and prostaglandins, are all mediated mainly/exclusively by TNF-R55. TNF-R75 appears to play a more prominent role in the induction of synthesis of T lymphocytes. All of the biological activities mediated by TNF-R75 can also be triggered via TNF-R55, and usually at much lower densities of receptors. TNF-R75 thus appears to play more of an accessory role, mainly to enhance effects mediated via TNF-R55. 

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Recombinant soluble TNF-RI-IgGl fusion protein Etanercept, Enbrel is a chimeric molecule consisting of the extracellular domain of the TNF receptor I (TNF-RI) and the Fc portion of human IgGl. Two Fc domains are bound to each other via disulfide bonds, thereby yielding dimers with two binding sites for the TNF trimer. Etanercept binds with high affinity to extracellular TNF and reduces TNF activity. Etanercept is not effective in Crohn s disease, possibly because it does not lead to destiuction of membrane TNF-a expressing cells. Indications and side effects are similar to those of Infliximab and Adalimumab. 

Soluble receptor constructs Etanercept This genetically engineered drug consists of the extracellular-part of the TNF-receptor type I and the Fc portion of human IgG. Its application in rheumatoid arthritis mirrors that of infliximab. 

Tumor necrosis factor receptor associated factors are a group of at least 6 proteins (TRAF 1-6), which are major signal transducers for the TNF receptor superfamily and the the interlukin-1 receptor/toll-like receptor (IL-1R/ TLR) superfamily. TRAF proteins are characterized by the presence of the TRAF domain at the the C-terminus,... 

Tumor Necrosis Factor a TNF Receptor Superfamily Cytokines Inflammation... 

Hyperphosphorylation of ERAK-1 by itself and ERAK-4 causes ERAK-1 to dissociate from the membrane-bound complex. Tumour necrosis factor (TNF) receptor-associated factor-6 ( TRAF-6), a cytoplasmic protein, is activated by ERAK-1 and with TAB-2, another cytoplasmic protein, activates transforming growth factor-P (TFG-P)-activating kinase (TAK-1). During this process both TRAF-6 and TAK-1 become ubiquitinated. TAK-1 then promotes activation of the IkB kinases, or the IKK family, EKKa and EKK 3 (found in a complex with NFicB-essential modulator [NEMO]), which phosphorylate the IkB family, notably IkB-u. IkB-u is an inhibitor of NFkB as it sequesters NFkB in an... 

TNF Receptor Superfamily Table appendix Receptor Proteins... 

Commercially available dtugs used for therapeutic therapy comprise up to date mainly injectable monoclonal antibodies like Infliximab (Remicade ) and Adalimumab (Humira ) or TNF-receptor derivatives like Etanercept (Enbrel ) (Fig. 3). One possible way of action of these reagents is the neutralization of TNF, thereby blocking its inflammatory effects and dampening (auto)immune responses [3, 4]. 

Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies integrating mammalian biology. Cell 104 487-501... 

TNF Receptor Associated Factors TNF Receptor Superfamily Tocolytics Tolerance... 

Etanercept is a recombinant form of human tumor necrosis factor receptor.24 Etanercept provides a therapeutic effect by binding to soluble TNF and preventing its binding with TNF receptors. It is administered subcutaneously once or twice weekly noticeable symptomatic improvement is seen in 1 to... 

TNF is produced and secreted by activated cells within minutes following contact with LPS, reaching peak levels at 90-120 minutes after the admnistration of Escherichia coli endotoxin in human volunteers (M27). Van Deventer et al. (D15) could not detect serum TNF levels during experimental endotoxemia. Even during continuous intravenous administration of recombinant TNF (rTNF), serum TNF rapidly becomes undetectable (M27). It has been proposed that circulating soluble TNF receptors (sTNF-Rs) may be an important down-regulating mechanism (G10). 

G10. Girardin, E., Roux-Lombard, P Grau, G. E., Suter, P., and Gallati, H., and Dayer J. M. The J5 Study Group. Imbalance between tumour necrosis factor-alpha and soluble TNF receptor concentrations in severe meningococcaemia. Immunology 76,20-23 (1992). 

Immune expulsion of T. spiralis is clearly Th2- and, specifically, IL-4-dependent. However, contrary to expectations, enteropathy (as assessed by changes in villus/crypt ratios) is regulated by IL-4 and not IFN-y (Lawrence et al., 1998). Moreover, the usual severe pathology is not induced in p55 TNF receptor (TNF-R1) gene-deficient mice, which nevertheless expelled... 

Joyce, D.A. and Steer, J.H. (1996) IL-4, IL-10 and IFN-gamma have distinct, but interacting, effects on differentiation-induced changes in TNF-alpha and TNF receptor release by cultured human monocytes. Cytokine 8, 49-57. 

Pender, S.L., Fell,J.M., Chamow, S.M., Ashkenazi, A. and MacDonald, T.T. (1998) A p55 TNF receptor immunoadhesin prevents T cell-mediated intestinal injury by inhibiting matrix metalloproteinase production. Journal of Immunology 160, 4098-4103. 

Piguet, P.F., Vesin, C., Guo, J., Donati, Y. and Barazzone, C. (1998) TNF-induced enterocyte apoptosis in mice is mediated by the TNF receptor 1 and does not require p53. European Journal of Immunology 28, 3499-3505. 

Mammalian cell suspension cultures are the preferred choice for large-scale recombinant protein production in stirred-tank bioreactors. The most widely used systems are Chinese hamster ovary (CHO) cells and the murine myeloma fines NSO and SP2/0. In half of the biological license approvals from 1996-2000, CHO cells were used for the production of monoclonal antibodies and other recombinant glycosylated proteins, including tPA (tissue plasminogen activator) and an IgGl fusion with the tumor necrosis factor (TNF) receptor, the latter marketed as Enbrel [7]. 

The exact molecular mechanisms by which TNF-induced signal transduction are mediated remain to be characterized in detail. Oligomerization of the receptors is often followed by their phosphorylation, most likely by accessory kinases that associate with the intracellular domain of the receptor (neither receptor type displays intrinsic protein kinase activity). The existence of several phosphoproteins capable of associating with (the intracellular domain of) TNF-R55 and TNF-R75 have also been established. Following clustering of the TNF receptors, these... 

One such product (tradename Beromun) has been approved for general medical use (Box 9.2). Most clinical interest in TNF, however, now centres around neutralizing its biological effects in situations where overexpression of TNF induces negative clinical effects. TNF has been firmly implicated in mediating many of the adverse effects associated with dozens of diseases (Table 9.7). Administration of anti-TNF monoclonal antibodies or soluble forms of the TNF receptor should help reduce the severity of many of the symptoms of these diseases. 

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