Tumor necrosis factor inflammation

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

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. 

Inflammatory cytokines have been implicated in the pathophysiology of HF.9 Several proinflammatory (e.g., tumor necrosis factor-a [TNF-a], interleukin-1, interleukin-6, and interferon-y) and anti-inflammatory cytokines (e.g., interleukin-10) are overexpressed in the failing heart. The most is known about TNF-a, a pleiotrophic cytokine that acts as a negative inotrope, stimulates cardiac cell apoptosis, uncouples 3-adrenergic receptors from adenylyl cyclase, and is related to cardiac cachexia. The exact role of cytokines and inflammation in HF pathophysiology continues to be studied. 

Eosinophils may be increased in some patients, particularly during exacerbations. Activated inflammatory cells release a variety of mediators, most notably leukotriene B4, interleukin-8, and tumor necrosis factor-a (TNF-a). Various proteinases, such as elastase, cathepsin G, and proteinase-3, are secreted by activated neutrophils. These mediators and proteinases are capable of sustaining inflammation and damaging lung structures. 

The inflammatory response in UC is propagated by atypical type 2 helper T cells that produce proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF).7 As discussed previously, a genetic predisposition to UC may partially explain the development of excessive colonic and rectal inflammation. The finding of positive perinuclear antineutrophil cytoplasmic antibodies (pANCA) in association with the human leukocyte antigen (HLA)-DR2 allele in a large percentage of patients with UC supports this theory.4,12... 

Multiple factors play a role in the development of AOM. Viral infection of the nasopharynx impairs eustachian tube function and causes mucosal inflammation, impairing mucociliary clearance and promoting bacterial proliferation and infection. Children are predisposed to AOM because their eustachian tubes are shorter, more flaccid, and more horizontal than adults, which make them less functional for drainage and protection of the middle ear from bacterial entry. Clinical signs and symptoms of AOM are the result of host immune response and damage to cells caused by inflammatory mediators such as tumor necrosis factor and interleukins that are released from bacteria.4... 

Zl. Van Zee, K. J., Kohno, T., Fischer, E Rock, C. S., Moldawer, L. L., and Lowry, S. F., Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor-a in vitro and in vivo. Proc. Natl. Acad. Sci. USA. 89,4845-4849 (1992). 

Local inflammatory changes occur in the joint capsule and synovium. The synovium becomes infiltrated with T cells, and immune complexes appear. Crystals or cartilage shards in synovial fluid may contribute to inflammation. There are also increased levels of interleukin-1, prostaglandin E2, tumor necrosis factor-a, and nitric oxide in synovial fluid. Inflammatory changes result in effusions and synovial thickening. 

Tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6 are proinflamma-tory cytokines important in the initiation and continuance of inflammation. 

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). 

Tumor Necrosis Factor There are two types of tumor necrosis factor TNF-a and TNF- 8. Of the two, TNF-a has been studied in more detail. TNF-a is a 157 amino acid polypeptide. It is a mediator of immune regulation, including the activation of macrophages and induction of the proliferation of T cells. Another TNF-a function is its cytotoxic effects on a number of tumor cells. Recent research, however, concentrates on its property in the stimulation of inflammation, particularly in the case of rheumatoid arthritis. Clinical trials are being conducted with drugs to block TNF-a with anti-TNF-a monoclonal antibodies. These antibodies target the excessive levels of TNF-a in the synovial fluid of joints and provide relief to sufferers of rheumatoid arthritis (Exhibit 4.10). 

Tumor necrosis factor-a (TNF-a) is a critical mediator of inflammation in autoimmune diseases like Crohn s disease and rheumatoid arthritis. Infliximab binds TNF-a and prevents its binding to the TNF receptor for treatment of these diseases. 

Etanercept (Enbrel ) is an engineered protein that combines the tail of an antibody with a part of the receptor for tumor necrosis factor (TNF). TNF is one of the cell-damaging proteins involved in inflammation. It got its name because the first thing scientists discovered that it did was kill cancer cells. Killing cancer cells is only one of its skills, however, and that may be something that happens... 

Tumor necrosis factor (TNF)—One of the cell-damaging proteins involved in inflammation, named because it appeared to kill cancer cells in the laboratory. Drugs for some autoimmune diseases like rheumatoid arthritis and Crohn s disease are designed to target TNF. 

Etanercept is a recombinant human soluble tumor necrosis factor-alpha (TNFo ) receptor fusion protein that binds to TNFo and decreases its role in disorders involving excess inflammation. It is approved for subcutaneous use in the treatment of patients with moderate to severe active rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing arthritis and plaque psoriasis. To the adverse reactions mentioned for infliximab, rare reports of congestive heart failure should be added. 

Mecfianism of Action A monoclonal antibody that binds specifically to tumor necrosis factor (TNF) alpha, blocking its interaction with cell surface TNF receptors, Tfier-apeutic Effect Reduces inflammation, tenderness, and swelling of joints slows or prevents progressive destruction of joints in rheumatoid arthritis. 

Cytokines are proteins that serve as signal molecules in cell-cell communication, and as such, perform a central and very diverse function in growth and differentiation of an organism. Representatives of cytokines control proliferation, differentiation and function of cells of the immune system and of cells of the blood-forming system. Furthermore, they are involved in processes of inflammation and in the neuronal, hema-poetic and embryonal development of the organism. Known cytokines include the interleukins (IL), erythropoietin, growth hormone, interferons (INF) and tumor necrosis factor (TNF) (see Table 8.1). A review of cytokines and cytokine receptors is to be found in HiU and Treisman, (1995) Taniguchi et al., (1995) and Moutoussamy et al., (1998). 

---