Tumor necrosis factor (TNF) is a multifunctional proinflammatory cytokine, TNF-alpha, secreted predominantly by monocytes/macrophages that has effects on lipid metabolism, coagulation, insulin resistance, and endothelial function.
The TNF gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNFs) superfamily.
TNFA is mainly secreted by macrophages. TNFA can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR.
TNFA is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation.
Human TNF-alpha is a 233 aa residue, nonglycosylated polypeptide that exists as either a transmembrane or soluble protein. When expressed as a 26 kDa membrane bound protein, TNF-alpha consists of a 29 aa residue cytoplasmic domain, a 28 aa residue transmembrane segment, and a 176 aa residue extracellular region.
The soluble protein is created by a proteolytic cleavage event via an 85 kDa TNF-alpha converting enzyme (TACE), which generates a 17 kDa, 157 aa residue molecule that normally circulates as a homotrimer.
Normal levels of circulating TNF are reported to be in the 10-80 pg/mL range. While both membrane-bound and soluble TNF-alpha are biologically active, soluble TNF-alpha is reported to be more potent. Mouse to human, full-length TNF-alpha shows 79% aa sequence identity. Unlike human TNF-alpha, mouse TNF-alpha is glycosylated.
The variety of cell types known to express TNF-alpha is enormous and includes macrophages, CD4+ and CD8+ T cells, adipocytes, keratinocytes,46 mammary and colon epithelium, osteoblasts, mast cells, dendritic cells, pancreatic beta-cells, astrocytes, neurons, monocytes, and steroid-producing cells of the adrenal zona reticularis.
Pathology
TNFA 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.
Function
Tumor necrosis factor alpha (TNFalpha) is a potent proinflammatory cytokine that plays an important role in immunity and inflammation, and in the control of cell proliferation, differentiation and apoptosis.
TNFalpha is also the founding member of a still growing family of cytokines with diverse bioregulatory functions.
TNFalpha-induced cellular responses
Binding of TNFalpha to its two receptors, TNFR1 and TNFR2, results in recruitment of signal transducers that activate at least three distinct effectors. Through complex signaling cascades and networks, these effectors lead to the activation of caspases and two transcription factors, AP-1 and NF-kappaB.
See also
References
Takei Y, Laskey R. Interpreting crosstalk between TNF-alpha and NGF: potential implications for disease. Trends Mol Med. 2008 Sep;14(9):381-8. PMID: 18693138
Holtmann MH, Neurath MF. Differential TNF-signaling in chronic inflammatory disorders. Curr Mol Med. 2004 Jun;4(4):439-44. PMID: 15354874
Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 2001 Sep;11(9):372-7. PMID: 11514191