Tumor necrosis factor-alpha and its inhibition strategies: Review article

Abstract

Tumor necrosis factor-alpha (TNF-?) is a pro-inflammatory cytokine produced by a variety of cells, including hematopoietic and non-hematopoietic cells, malignant cells, macrophages, B lymphocytes, T lymphocytes, natural killer cells, neutrophils, astrocytes, endothelial cells, and smooth muscle cells. TNF-? is a homo-trimeric molecular whose individual subunits are composed of antiparallel beta-sheets, forming a regular triangular prism shape. TNF-? binds to three receptor molecules through its receptor-binding sites, which are at the base of its pyramid structure. Biological responses to TNF-? are mediated through two different receptors: TNFR1 and TNFR2. These receptors are transmembrane glycoproteins with extracellular domains containing multiple cysteine-rich repeats that are structurally and functionally homologous, and the intracellular domains that are discrete and transduce their signals through both overlapping and distinct pathways. However, though TNF-? was initially discovered as an anti-tumor agent, it has been revealed that TNF-? and other ligands of this family are involved in some diseases like cancer, neurological, pulmonary, cardiovascular and autoimmune diseases and metabolic disorders. In general, TNF-? activates the control systems involved in cell proliferation, differentiation, inflammation and cell death, and the regulation of immune system. Although a normal level of TNF-? is very important for the regulation of immune responses, the persistence of the immune response as a result of inappropriate and excessive production of TNF-? can cause some inflammatory or autoimmune diseases. Accordingly, either neutralization TNF-? or blockade of its receptors using TNF-? inhibitors can be an effective therapeutic strategy to prevent or treat such inflammatory diseases. Several methods have been used to inhibit TNF-?, including the production of chimeric or fully human antibodies, soluble TNF-? receptors, or anti-TNF-? small molecules. The two previous agents are mostly capable of inhibiting the binding of TNF-? to its associated receptors, while anti-TNF-? small molecules, in addition to the above, inhibit the biosynthesis of TNF-? by blocking TNF-? mRNA biosynthesis, through the inhibition of its post-translational processing, or by blocking TNF-? receptors. Therefore, in this review article, we discuss the structure and characteristics of TNF-? and its related receptors: TNF-? signaling, TNF- ?-mediated inflammatory diseases as well as TNF-? inhibition strategies. © 2017, Tehran University of Medical Sciences. All rights reserved.