Tumor necrosis factor -like activity

Human tumor necrosis factor (TNF) (Fig. 1) is a hormone-like proinflammatory peptide belonging to the group of cytokines. It is mainly produced by cells of the immune system in response to infection, inflammation, or cell damage. Disregulated TNF is an important factor in many pathological situations, like sqDsis, rheumatoid arthritis, inflammatory bowel disease (Crohn s disease), and Cachexia. The cytotoxic activity of TNF is of interest in development of new antitumoral strategies. 

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],... 

Tumor necrosis factor a (TNF-a) is a multifunctional cytokine produced by activated monocytes-macrophages. TNF-a is one of the most potent osteoclastogenic cytokines produced in inflammation, and, in addition, TNF-a induces IL-1 synthesis. Like the other known stimulators of bone resorption, it acts through osteoblastic cells however, it has been demonstrated that TNF-a is able to induce osteoclast formation from stromal-depleted macrophages, with potency similar to that of RANKL (Kobayashi et al. 2000). TNF-a is able to induce bone resorption in vitro (Thomson et al. 1987) as well as in vivo (Koning et al. 1988). Osteoclasts induced by TNF-a have the capacity to form resorption pits on dentine slices only in the presence of IL-la. TNF-a, together with IL-1, plays an important role in bone resorption in inflammatory diseases (Kobayashi et al. 2000). Inhibition of TNF by TNF binding protein (TNFbp) completely prevents bone loss and osteoclast formation (Kimble et al. 1997). 

Some new materials perspective for advanced biomedical technologies, especially carbon nanoparticles like fullerenes, are potentially mutagenic, carcinogenic and immunogenic [16,65], Therefore, standard tests of the morphological transformation of Syrian hamster embryonic cells in cultures on these materials (described in detail by [68,69]) can be performed. Immune activation of bone and vascular cells on the materials can be estimated by increased concentration of immunoglobulin and selectin adhesion molecules (ICAM-1, VCAM-1, ELAM-1), which bind cells of the immune system [15,16,18,19,23], as well as by the production of cytokines, such as tumor necrosis factor alpha or interleukins beta [55],... 

Endotoxicity results from the interaction of a bacterial cell envelope component (e.g., LPS or PG with a cell surface receptor constituting part of the nonspecific immune system, (i.e., a toll-like receptor on white blood cells). This results in the production of cytokines [e.g., interleukin 1 (IL-1) or tumor necrosis factor (TNF)] as part of an intracellular enzyme cascade which can cause severe tissue injury. Bioassays or immunoassays can be used to detect such reactions respectively. As noted above the most widely used bioassay is the LAL assay. A lysate of amoebo-cytes of the horseshoe crab (Limulus) contains an enzymatic clotting cascade which is activated by extremely low levels of LPS (nanogram levels or lower). There are variants of this assay that can detect PG, but they are not as widely used. As noted above, other bioassays employ cultured cell lines that respond to LPS or PG, respectively. Unfortunately bioassays are highly amenable to false positives (from the presence of cross-reactive substances) or false negatives from inhibition (by contaminants present in the sample) [10]. A detailed discussion of these assays is beyond the scope of this chapter and has been reviewed elsewhere [1]. 

Figure 22.2 Cellular activation by CpG DNA. CpG DNA directly activates dendritic cells (DCs), monocytes and macrophages, to express increased levels of co-stimu-latory molecules, to increase antigen presentation, and to secrete high levels of chemokines and cytokines, such as interleukin 12 (IL-12), interferon-a(IFN-a), and tumor necrosis factor-a (TNF-a), and monocytes and macro-phages have increased antibody-dependent cellular cytotoxicity (ADCC) activity. NK cells are induced to express IFN-7 by these cytokines acting in concert with CpG, and have increased lytic activity. B cells rapidly produce IL-b and IL-10 and express increased levels of costimulatory molecules. B cells rapidly enter the cell cycle and become resistant to some forms of activation-induced cell death. T cells are not directly activated by CpG, but because of the T helper 1 (Thl)-like cytokine environment, and the increased antigen presenting cell (APC) activity, antigen-specific Thl cells and cytotoxic T lymphocytes (CTL) are generated.

The tumor necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins that are structurally related in their extracellular domains and specifically activated by the corresponding superfamily of TNF-like ligands (Locksley et al, 2001). Members of this receptor superfamily are widely distributed and play important roles in many crucial biological processes such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis. Agents that manipulate the signaling of these receptors are being used or showing promise towards the treatment and prevention of many human diseases (Ashkenazi and Dixit, 1998 Leonen, 1998 Newton and Decicco, 1999). 

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