Tumor+Necrosis+Factor

= = =Tumor Necrosis Factor- Kill my Tumor!= =Katie O'Brien=

Abstract:
Tumor Necrosis Factor (TNF) is a cytokine of the immune system characterized by modulating cell death, proliferation, and inflammation. Within this article I will breifly explain what a cytokine is, groups of cytokines within our immune system, metabolic pathways of TNF, cell death, and medical treatments and research used today.

Background:
At the cellular level within our immune system we have molecules that act as cellular communicators, known as cytokines. A cytokine is defined as any of a group of small, short-lived proteins that are released by one cell to regulate the function of another cell within the immune response. Cytokines work towards communication with white blood cells (nearly all cells are able to produce such chemical messengers(Tortora). ** Cytokine **s typically are not stored within the cell but instead are synthesized “on demand,” often in response to another ** cytokine ****.** Once secreted, the ** cytokine ** binds to a specific cellular receptor on the surface of the target cell causing an event that triggers a signaling cascade inside that cell. The signal ultimately reaches the nucleus, where the effects of the ** cytokine ** are manifested in changes in gene transcription and protein expression. Cytokines can be divided into five categories: interleukins, interferons, colony-stimulating factors, growth factors, and tumor necrosis factor (Encyclopedia Brittanica).

Interleukins are made by leukocytes and are known to regulate cell growth, differentiation, motility, and also inflammation. Fifteen different types of interleukins are known, and are named IL-1 through IL-15. The immunological functions of most of the interleukins are known to some degree. (Encyclopedia Brittanica)

Interferon was named for its ability to interfere with viral proliferation. The various forms of interferon are the body’s most rapidly produced and important defense against viruses. Interferons can also combat bacterial and parasitic infections, inhibit cell division, and promote or impede the differentiation of cells. They are produced by a variety of the body’s cells. (Encyclopedia Brittanica)

Colony stimulating factors and growth factors are a group of cytokines that stimulate cell growth and differentiation to the growth of specific tissues. (Encyclopedia Brittanica)

TNF:
Tumor necrosis factor (TNF) is a family of more than 18 cytokine messenger proteins that play a role in inflammation and cellular apoptosis. At the cellular level, all cells have TNF receptors, or a subset of TNF receptors, some TNF’s bind to some receptors, while others bind to one or many others. (Guarr).The TNF gene has been isolated to chromosome 6p21.3, spans about 3,000 base pairs and contains 4 exons. The last exon codes for more than 80% of the secreted protein (G. Nedwin).



Physiologically TNF works by binding to one of at least thirty different types of TNF receptors on a cells surface, classified as having a death domain (DD) or in some tissue cell types not having a DD. The DD initiates a series of metabolic pathways leading to initiate cellular apoptosis, expression of NFxB, or AP-1 (Guar).

One example of a pathway is when TNFDD1 initiates several other intracellular molecules such as TRADD, to FADD (Associated death domain) to FLICE (FADD-like ice) concluding with caspase-3 resulting in apoptosis (Guar).



__NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)__ is a protein complex that controls the transcription of DNA. NF-κB is found in almost all cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation , oxidized LDL , and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection thus, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development (TD Gillmore).

__AP-1__ is a transcription factor that regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections. AP-1 in turn controls a number of cellular processes including differentiation, proliferation, and apoptosis ( M. Ameyar ).



Apoptosis is described by its morphological characteristics, including cell shrinkage, membrane blabbing, chromatin condensation and nuclear fragmentation. Apoptosis, or programmed cell death, is one of the major control mechanism by which cells undergo self destruction, if DNA damage is not repaired. Also, Apoptosis is important in controlling cell number and proliferation as part of normal growth and development (S. Low).



The theory of an anti-tumoral response of the immune system discovered in 1968, Dr. Gale A Granger, reported a cytotoxic factor produced by lymphocytes and named it lymphotoxin (LT). In 1975 Dr. Lloyd Old from Memorial Sloan-Kettering Cancer Center, New York, reported another cytotoxic factor produced by macrophages, and named it tumor necrosis factor (TNF).(E. Carswell). In 1984 cDNA encoding proved LT and TNF to be similar thus renaming each to TNF-a and TNF-b. (D. Pencia), the two major cytokines noted as TNF. (Guar)

Much is still not understood about each and every different TNF and pathway, we do know that they all activate NF-kB, a transcription factor that has been implicated in suppression of aptosis, cell survival, proliferation, viral replication, bone reabsorbtion, tumor genesis, and metastasis.

Scientist's hope was to find a way to combat cancer upon the discovery of this protein. Unfortunately we have yet to understand how exactly it works. The TNF family of cytokines is still under study because it does so many things in cellular regulation and in conjunction with interleukins. What we do know is there is a precise homeostasis within the regulation of inflammation and cell apoptosis and that balance must be kept or severe inflammatory disease will occur such as septic shock or such illnesses as tuberculosis, viral infections, and other autoimmune disorders (M. Centocar). Thus implementing it in cancer treatments is still underway. We have however been able to uses TNF-inhibitors to combat many autoimmune diseases.



In a November 2008 study of 24 patients concluded the use of anti-TNF treatments including intravenous Infliximad or Adalimumab medications for the treatment of Crohn’s disease. Patients were rated moderate to severe in their disease and were also administered different combinations of antibiotics, immunosuppressant’s, and corticosteroids with the anti-TNF treatment. The study concluded with 11 patients going into remission (46%), partial response to 6 patients (25%), and no notable difference in the remaining 7 patients (J. Paredas).

Infliximab works by binding to tumour necrosis factor alpha.Infliximab is an artificial antibody originally developed from a mouse antibody. Infliximab can cost $19,000 to $22,000 a year per patient wholesale, according to Centocor. Drug name Remicade is typically covered under major medical insurance and is usually administered intravenously over the course of six to eight weeks. This particular drug was approved by the FDA ( U.S. Food and Drug Administration) for the treatment of psoriasis, Crohn's disease, rheumatoid arthritis, and ulcurative colitis in 1998 (FDA).

Another recent study involving incarcerated patients suffering from rheumatoid arthritis or crohn’s disease being treated with anti-TNF treatments showing signs of tuberculosis. All cases involved patients having a high risk factor in exposure to //Mycobacterium tuberculosis,// receiving anti-TNF treatments, and becoming ill approximately two weeks after treatment. Some patients discontinued the anti-TNF treatment while treating M //tuberculosis// while others added glucocorticoids in their treatments. Doctors are now taking extra precautions in the use of anti-TNF treatments with patients possible being exposed to M. //tuberculosis// (M. Centocor).



A recent study involv ing Iranian black tea and cowslip extracts concluded inducing TNF-a secretion from mouse macrophage cell cultures. I was drawn to this article because of the use of Iranian black teas and cowslip extracts in traditional medicine. The study concluded synergistic effects of both Iranian black tea and cowslip extract being used in conjunction for maximum TNF-a secretion. Current studies show biological effects of TNF as anti-tumoral and antimicrobial while the tea is known to have many catechins that help encourage inter-leukines and TNF production (M. Nadi).

Scientists attempts to combat cancer using these little chemical messengers of our immune system is yet still underway. We have made leaps and bounds in discovering and trying to understand our immune systems language with these messengers and yet we have more to embark to fully understand cancer, tumors, and the body’s defense with TNF.

Works Cited
 * M. Ameyar, (August 2003). "A role for AP-1 in apoptosis: the case for and against". //Biochimie// 85 (8): 747–52
 * E. Carswell [|"An endotoxin-induced serum factor that causes necrosis of tumors"] . Proc. Natl. Acad. Sci. U.S.A.1972. V.9: 3666–70
 * M. Centocor. “Tuberculosis Associated with Blocking Agents Against Tumor Necrosis Factor-Alpha-California.” 2002-2003. Morbidity & Mortality Weekly Report. Vol. 53, No. 30. P. 683-686.
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 * Guar. “Regulation of proliferation, survival and apoptosis by members of the TNF superfamily.” Biochemical Pharmacology. Elsevier Inc. March 2003 pgs 1403-1408.
 * T.D. Gillmore, (2006). "Introduction to NF-κB: players, pathways, perspectives". //Oncogene// **25** (51): 6680–4. http://en.wikipedia.org/wiki/NF-%CE%BAB.
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 * M, Nadi. February 2009. “Iranian Black Tea and Cowslip Extract Induce Tumor Necrosis Factor-Alpha Secretion from Mouse Macrophage Cell Culture.” Iranian Journal of Pharmaceutical Research 2010. 9(1):83-87.
 * G. Nedwin (1985). [|"Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization"]. //Nucleic Acids Res.// **13** (17): 6361–73.
 * J. Paredas. “Abdominal Sonographic Changes After Antibody to Tumor Necrosis Factor (Anti-TNF) Alpha Therapy in Crohn’s Disease.” Digest of Discovery Science (2010) 55:404-410.
 * D. Pencia. “Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin". Nature 1984. V. 312.
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