Lymphotoxin (LT) was first discoveredcell factorOne, LT islymphocyteAntigen orMitogenAfter activation of isostimulations and in some tumorsAutoimmune diseaseIt is a kind of cytokine secreted under the condition of.Although LT andtumor necrosis factorα（TNF-α) They are similar in molecular structure and active region, and their biological activities are similar, but their differences are also obvious: LT specific LT β and its receptor, two cytokinestumor cellThere were also differences in the binding ability and killing activity in vivo and in vitro.In recent years, with the successful development of LT genetic engineering products, LTAntineoplastic drugsWith the deepening of experimental research, LT may be a kind of cytokine with better curative effect.
Lymphotoxin[1](LT) is the first discoveryCellsOne of the factors, LT islymphocyteAntigen orMitogenAfter activation of isostimulations and in some tumorsAutoimmune diseaseIt produces secretion under the condition ofcell factor。Although LT andtumor necrosis factorα (TNF - α) is similar in molecular structure and active region, and their biological activities are similar, but their differences are also obvious: LT specific LT β and its receptor, two cytokinestumor cellThere were also differences in the binding ability and killing activity in vivo and in vitro.
According to the different sources of TNF, the TNF produced by monocytes/macrophages is called tumor necrosis factor alpha (TNF - α), and the TNF produced by T cells is called tumor necrosis factor beta (TNF - β), or LT.[2]
LT can be divided into membrane bound and soluble forms: membrane bound LT is distributed on the cell membrane in the form of a complex formed by the combination of the subunits of LT - α and LT - β;The soluble form secreted out of the cell is called LT - α, and the secretory LT - α is anchored by non covalent binding with LT - βcell surface, forming the surface LT together.LT - β is a 33 × 10threeA membrane protein molecule that can provide sites for LT - α binding.[3]
In recent years, with the successful development of LT genetic engineering products and the deepening of experimental research on LT as an anti-tumor drug, it shows that LT may be a kind of drug with good curative effectcell factor。
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In 1967, Ruddle and Waksman discovered lymphotoxin when they studied delayed hypersensitivity.Lymphotoxintumor necrosis factorβ，Tumor necrosis factor alpha (TNF - α) and tumor necrosis factor alpha (TNF - α) are two closely related cytokines, both belong to the TNF family, and their soluble forms are trimer bound to the sameCell surface receptor, producing completely similar but different effects.One of them is that they can directly kill some tumor cells, which is why they are named.LT and TNF - α have many similar biological functions, such as killing a variety of tumor cells, participating in the regulation of immune response, regulating inflammatory response, and inducing antigen expression of a variety of differentiated cells.[4]LT and tumor necrosis factor - α (TNF - α) are two closely related cytokinestransfer factor(TNF) family, both are very similar in gene location, molecular structure, receptor affinity and biological function.
Structural characteristics
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The human lymphotoxin and tumor necrosis factor alpha genes are two closely linked single copy genes, which are located between chromosome 6p23-6q12.Carrol et al. confirmed that these two genes are located in the major histocompatibility complex (MHC) gene cluster, and the distance between the complement C2 and HLA-B sites is only 1.1 kb.These two genes of mice are located on chromosome 17 and closely linked to mouse MHC.The total length of human LT gene is 3037bp, and the total length of TNF - α gene is 3634bp. They are composed of three introns and four exons.The signal peptide of LT consists of 34 amino acids, and the mature protein contains 171 amino acids;The signal peptide of TNF-a has 76 amino acids, and the mature protein has 157 amino acids.[4]
Similar to TNF - α, lymphotoxin also has two forms: membrane binding and soluble. The soluble form secreted out of cells is called Llb (that is, the lymphotoxin commonly referred to in the field of genetic engineering);The membrane bound lymphotoxin is distributed on the cell membrane in the form of a complex formed by the combination of the subunits of LT α and LT β. LT β is a 33KD membrane protein molecule that can provide a site to bind to LT α.
LT beta receptor
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LT - β R is a member of the TNF receptor superfamily (TNFRSF), which regulates tissues and organsInternal environment steady stateImportant intermediate medium.The human LT - β R gene (LT - β R or TNFRSF - 3) is located on the autosomal (CHR) 12 and encodes similar genes to other TNFRSF members, namely, TNFR - 1 (TNFRSF1A) and CD27 (TNFRSF12A).[5]LT - β R gene encodes 435 amino acids of type I glycosylated protein, which consists of three main domains: extracellular domain (ECD), transmembrane domain (TMD) and intracellular domain (ICD), also known as cytoplasmic domain (CD).
LT - β R can activate NF - κ B pathway and promote inflammation.LT - α and LT - β are expressed in activatedlymphocyte、dendritic cell Lymphoid tissue induced cells.The corresponding receptor (LT - β R) is widely expressed inendothelial cells、Fibroblast、epithelial cells、monocyteAnd dendritic cells.[6]It has been found that LT - β R involves many processes, such as liver regeneration, lipid balance,Autoimmune disease, development of secondary lymphoid organs and spleen.stayimmune systemLT - β R plays a signal transmission function. Once its regulation is abnormal, it will lead to autoimmune and inflammatory diseases, including rheumatoid arthritis,Sjogren's syndrome，Autoimmune pancreatitis, hepatitis, colitis.
biological function
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Lymphotoxins have a wide spectrum of anti-tumor and significantly inhibit tumor growth.
