Tumor necrosis factor receptor mechanism

In a study investigating the allometric relationships of pharmacokinetic parameters for five therapeutic proteins, the allometric equations for clearance and volumes of distribution, however, were found to be different for each protein [102]. This variability was attributed to possible species specificity and immune-mediated clearance mechanisms. Species specificity refers to the inherent differences in structure and activity across species. Minute differences in the amino acid sequence may render an agent inactive when administered to foreign species, and may even generate an immunogenic response. Immunogenicity has been clearly demonstrated in a study with the tumor necrosis factor receptor-immunoglobulin fusion protein lenercept. This all-human sequence protein elicits an immune response in laboratory animals which ultimately results in the rapid clearance of the protein [103]. 

Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M (2001), Activation of caspase-12, an endoplasmic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress, J. Biol. Chem. 276 13935-13940. 

Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP (1999) Tumor necrosis factor receptor and Eas signaling mechanisms. Aimu Rev Immunol 17 331—367. 

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

Mechanism of Action Aprotein that binds to tumor necrosis factor (TNF), blocking its interaction with cell surface receptors. Elevated levels of TNF, which is involved in inflammatory and immune responses, are found in the synovial fluid of rheumatoid arthritis patients. Therapeutic Effect Relieves symptoms of rheumatoid arthritis. Pharmacokinetics Well absorbed after subcutaneous administration. Half-life 115 hr. 

New D. R., Maggirwar S. B., Epstein L. G., Dewhurst S., and Gelbard H. A. (1998). HIV-1 Tat induces neuronal death via tumor necrosis factor-a and activation of non-A-methyl-D-aspartate receptors by a NFfcB-independent mechanism. J. Biol. Chem. 273 17852-17858. 

Akama KT, Van Eldik LJ (2000) Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-Ibeta- and tumor necrosis factor-alpha (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor- and NFkappaB-inducing kinase-dependent signaling mechanism. J Biol Chem 275 7918-7924... 

---