The INDIVIDUALIST

A Wiki about biochemical individuality

Immunology

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Description

In medicine, tumor necrosis factor alpha (TNFα, cachexin or cachectin) is an important cytokine involved in systemic inflammation and the acute phase response.

History and nomenclature

TNFα was isolated in 1975 by Carswell et al as a soluble factor released by host cells that caused necrosis of a transplanted tumor, "sarcoma Meth A". Although TNFα does cause the necrosis of some tumors, it may stimulate the growth of others. In that sense, the name is somewhat of a misnomer.(1)

Structure

TNFα is a member of a group of other cytokines that all stimulate the acute phase reaction. It is a 185 amino acid glycoprotein peptide hormone, cleaved from a 212 amino acid-long propeptide on the surface of macrophages. Some cells secrete shorter or longer isoforms. Genetically it links to chromosome 7p21 in humans.

Physiology

TNFα is released by white blood cells, endothelium and several other tissues in the course of damage, e.g. by infection. Its release is stimulated by several other mediators, such as interleukin 1 and bacterial endotoxin. It has a number of actions on various organ systems, generally together with interleukin 1 and interleukin 6:

  • On the hypothalamus:
    • Stimulating of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH).
    • Suppressing appetite (hence its name "cachexin" - cachexia is severe weight loss in illness).
    • Fever.
  • On the liver: stimulating the acute phase response, leading to an increase in C-reactive protein and a number of other mediators.
  • It attracts neutrophils very potently, and helps them to stick to the endothelial cells for migration.
  • On macrophages: stimulates phagocytosis, and production of IL-1, oxidants and the inflammatory lipid, prostaglandin E2 (PGE2).
  • On other tissues: increasing insulin resistance.

A locally increasing concentration of TNFα will cause the cardinal signs of inflammation to occur: Heat, swelling, redness and pain.

Pharmacology

Inhibition of TNFα with a monoclonal antibody or a circulating receptor such as infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira) are used in modern treatment of various autoimmune disorders such as rheumatoid arthritis, Crohn's disease and psoriasis. Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are currently ongoing.

Such drugs may raise the risk of contracting tuberculosis or causing a latent infection to become active. Infliximab and adalimumab have label warnings which state that patients should be evaluated for latent TB infection and treatment should be initiated prior to starting therapy with these medications.

TNF or the effects of TNF are also inhibited by a number of natural compounds, including curcumin (an ingredient in turmeric) and catechins (in green tea).

Echinacea alkylamides modulate TNFA gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways.(2)

Genomics

TNF tumor necrosis factor (TNF superfamily, member 2)

Summary

  • Official Symbol: TNF
  • Name: tumor necrosis factor (TNF superfamily, member 2)
  • Gene type: protein coding
  • Gene name: TNF
  • Gene description: tumor necrosis factor (TNF superfamily, member 2)
  • Chromosome: 6; Location: 6p21.3
  • Organism: Homo sapiens
  • Gene aliases: DIF; TNFA; TNFSF2; TNF-alpha
Summary

This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, and cancer. Knockout studies in mice also suggested the neuroprotective function of this cytokine.

Discussion

One of the main immune system Growth Factors.

TNF-alpha is a critical part of the rejection process that occurs when someone is transfused with the wrong blood type. (3)

Low levels of TNF-alpha, comparable to those present physiologically, induced nucleus pulposus degradation. TNF-alpha may contribute to the degenerative changes that occur in disc disease. (4]

Single nucleotide polymorphism is associated with age of onset of schizophrenia. (5)

Synergistic interactions between the coagulation factor Xa (fXa) and the proinflammatory cytokines TNF, IL-1beta, and CD40L, leads to enhanced expression of Tissue Factor and E-selectin in endothelial cells. (6)

TNF-alpha behaves as a trigger of platelet activation through stimulation of the arachidonic acid pathway. (7)

Among host genetic factors contributing to H. pylori disease outcome, TNF-A -857 TT genotype favors duodenal ulcer. (8)

Blood TNF alpha concentrations are elevated in non-obese, non-diabetic Mexican Americans. (9)

A significant correlation between BMI and leptin was found in the two fat tissue compartments of both genders, but the correlation between BMI and TNFalpha was found only in subcutaneous fat tissue of women. (10)

TNFA promoter polymorphism is associated with susceptibility to endometriosis. (11)

Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors. (12)

Obese women, even those with morbid obesity, over-express TNFalpha in subcutaneous adipose tissue in proportion to the magnitude of the fat depot. (13)

In Polish TNF-alpha (-308A) allele carriers, obesity correlated with insulin resistance in females. (14)

Links

Attribution

References

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