Tumor Necrosis Factor (TNF) & Receptor Proteins

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Tumor Necrosis Factor (TNF) & Receptor Proteins

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Tumor Necrosis Factor (TNF) & Receptor Proteins Background

Tumor Necrosis Factor (TNF) is a cytokine that can directly kill tumor cells without obvious toxicity to normal cells. TNF is not heat-resistant and will be inactivated at 70℃ for 30 minutes. It is one of the most effective bioactive factors to kill tumor directly. Tumor necrosis factor can be divided into TNF-αand TNF-β, and about 30 kinds of TNF family are found in addition to these two types. umor necrosis factor (TNF) is a small molecular protein secreted by macrophages and its content in normal human serum is 4.3±2.8mg/L. TNF-α is secreted mainly by mononuclear macrophages. TNF-β is secreted primarily by activated T lymphocytes.

A schematic diagram of the effect of tumor necrosis factor on various cells Fig.1 A schematic diagram of the effect of tumor necrosis factor on various cells

Properties of TNF protein

  1. The human TNF-α precursor is composed of 233 amino acids (26 kDa), which contains signal peptides composed of 76 amino acid residues. Under the action of TNF-converting enzyme TACE, the signal peptides were removed to form mature TNF-α peptides with 157 amino acid residues (17 kDa). Because there is no methionine residue, there is no glycosylation site, in which cysteine at position 69 and 101 forms an intramolecular disulfide bond. Human TNF-α has 79% amino acid composition homology with mouse TNF-α, and the biological effect of TNF-α does not seem to have obvious species specificity. Recently, there are news reports that 155 amino acid human TNF-α with less 2 amino acids (Val, Arg) at the N-terminus has been expressed by genetic engineering technology, which has better biological activity and antitumor effect. In addition, there are genetic engineering methods that delete 7 amino acid residues at the amino terminal of the TNF-α molecule, and then change 8Pro, 9Ser, and 10Asp to 8Arg, 9Lys, and 10Arg, or change 157Leu to 157Phe at the same time. TNF-α has a 1000-fold increase in killing L929 cells in vitro compared to natural TNF, and the tumor hemorrhagic and necrotic effects in vivo are also significantly increased. The natural forms of TNF-α and β exerting biological effects are homotrimers.
  2. The human TNF-β molecule is composed of 205 amino acid residues and a signal peptide containing 34 amino acid residues. The mature TNF-β molecule is 171 amino acid residues and has a molecular weight of 25 kDa.
  3. Human TNF-β and TNF-α have 56% DNA homology and 36% homology at the amino acid level. X-ray crystal diffraction technology was used to prove that TNF is a dense trimer composed of three identical monomer subunits. The monomer subunits are wedge-shaped, and β-sandwich structures are formed by β-sheet folding.

The structure and function of the Tumor necrosis factor receptor (TNFR)

TNFR can be divided into two types: TNFR1 is expressed in all types of cells and plays a major role in cytolytic activity. TNFR2 is only expressed in immune and endothelial cells and is associated with signaling and T cell proliferation. Both TNFRS are glycoproteins, including extracellular, transmembrane, and intracellular regions. The extracellular region has 28% homology, but there is no homology in the cytoplasmic region, which may be related to the mediation of different signal transduction pathways. Several studies have confirmed that tumor necrosis factor exerts its biological activity mainly through interaction with TNF-R1. TNF protein binds to the extracellular region of TNF-R1 to induce tnf-r1 aggregation and release of death domain silencing (SODD), and TRADD then binds to the death domain of TNF-R1 to recruit more junction proteins, such as RIP, TRAF-2 and FADD. These adaptor proteins recruit other important proteins involved in signal transduction to function. At present, little is known about the structure and function of TNF-R2, but it lacks a death domain and therefore cannot promote the process of apoptosis. However, TNF-R2 can interfere with programmed cell death (PCD) by activating the NF-κB and JNK pathways or inhibiting TRAF-2.

Apoptosis induced by TNF-α combined with TNFR Fig.2 Apoptosis induced by TNF-α combined with TNFR

The distribution of TNFR

TNFR exists on the surface of a variety of normal and tumor cells. Generally, the number of receptors per cell is 500 ~ 5000 / cell. For example, ME-800 tumor cell line TNFR is about 2000 / cell, and Kd is 2 × 10-10M. The number and affinity of TNFR on different cell surfaces do not seem to be parallel to the cell's sensitivity to TNF-α.

Soluble tumor necrosis factor receptor

TNF-binding protein (TNF-BP) is a soluble form of TNFR. There are sTNFRⅠ (TNF-BPⅠ) and sTNFRⅡ (TNF-BPⅡ). It is generally believed that sTNFR has the function of limiting TNF activity or stabilizing TNF, and it also has an important regulatory role in the cytokine network. TNF-BP specifically binds TNF to inhibit TNF activity, such as inhibiting its cytotoxic activity and inducing IL-1 production, and can promote the growth of Meth A virus subcutaneously inoculated, which may be one of the mechanisms of tumor escape host anti-tumor. TNF-BP in normal human serum is 1-2 ng / ml, which can also be found in normal pregnancy urine. Its content increases during inflammation, endotoxemia, meningococcal infections, SLE, HIV infection, renal insufficiency, and tumors. Soluble TNFR can effectively reduce the pathological changes of adjuvant arthritis and septic shock.

Tumour necrosis factor signalling in health and disease Fig.3 Tumour necrosis factor signalling in health and disease

References:

  1. Chen G, Goeddel D V. TNF-R1 signaling: a beautiful pathway[J]. Science, 2002, 296(5573): 1634-1635.
  2. Tartaglia L A, Goeddel D V. Two TNF receptors[J]. Immunology today, 1992, 13(5): 151-153.
  3. Lee E G, Boone D L, Chai S, et al. Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice[J]. Science, 2000, 289(5488): 2350-2354.
  4. Beg A A, Baltimore D. An essential role for NF-κB in preventing TNF-α-induced cell death[J]. Science, 1996, 274(5288): 782-784.
  5. Mogi M, Harada M, Riederer P, et al. Tumor necrosis factor-α (TNF-α) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients[J]. Neuroscience letters, 1994, 165(1-2): 208-210.

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