Lymphotoxin α and coronary heart disease
Overview of lymphotoxin
Lymphotoxin (LT) is one of the earliest discovered cytokines. LT is a cytokine that secreted lymphocytes by stimulating activation of antigen or mitogen and in the case of some tumors and autoimmune diseases. Although LT and tumor necrosis factor alpha (TNF-α) in the molecular structure and activity of the region similar to the two of some biological activity similar, but their difference is also obvious: LT-specific LTβ and its receptor, two The binding ability of cytokines to tumor cells and the cytotoxic activity in vitro and in vivo are also different. In recent years, with the successful development of LT genetic engineering products, LT as an anti-tumor drug research continues to deepen, showing that LT may be a better effect of cytokines.
Lymphotoxin alpha function
Lymphotoxin alpha belongs to the family of tumor necrosis factor, which is a cytokine substance that regulates the inflammatory immune response and thus affects the differentiation of cells. Lymphotoxin alpha is a lymphoid factor that is produced mainly by activated T cells, including CD4 + and CD8 + T cells. The human lymphotoxin alpha gene is located on chromosome 6, and the lymphotoxin alpha molecule consists of 205 amino acid residue composition, containing 34 signal peptide, mature lymphotoxin α molecule 171 amino acid residues, the relative molecular mass of 25 000. Lymphotoxin alpha can closely bind to tumor necrosis factor receptor-1 (TNFR-1), tumor necrosis factor receptor-2 (TNFR-2) Combined with the same type of trimer in the form of secretion or binding in the cell membrane surface. Through the synthesis of lymphotoxin, lymphotoxin α and lymphotoxin β can form hetero-trimeric lymphotoxin α1, β2 or lymphotoxin α2, β1, they can and lymphotoxin β receptor binding, and lymphotoxin β receptor Usually in fibroblasts, epithelial cells, monocytes, dendritic cells, mast cells are expressed. LT-α and lymphotoxin β binding, through the lymphotoxin β receptor signaling, activation of nuclear transcription factor-κB (NF-κB) pathway, the gradual activation of inflammatory factors. Lymphotoxin secretion is regulated by cytokine-like substances and galectin-2, whereas galactinolin 2 is a binding ligand for lymphotoxin alpha that binds with tubulin alpha, LT-beta tubulin, mediates LT-α transport. In vitro experiments have shown that galectin 2 is inhibited and can be reduced or inhibited expression of lymphotoxin alpha.
The relationship between lymphotoxin α and coronary heart disease
With the completion of human genome sequencing, human beings have entered the post-genome era, and the study of genetic differences between individuals is one of the important elements of human gene sequencing. This difference is most common in single nucleotide polymorphisms (SNPs), that is, at the genome level by a single nucleotide mutation caused by DNA sequence polymorphism. It is this polymorphism caused by human hair, skin color, disease susceptibility and other aspects of the difference. At present, the SNP study of lymphotoxin α is one of the hotspots of cardiovascular disease.
Mizuno and other 73 atherosclerosis-related gene polymorphism analysis, and the corresponding 87 genotyping studies. Experimental results show that in the lymphotoxin αA252G this mutation, G allele carriers of acute myocardial infarction in patients with a significant increase in mortality.
PROCARDIS Association’s study of genetic susceptibility genes in coronary heart disease After genotyping of T26N mutations, the genotype-risk ratios for both coronary heart disease were compared with a heterozygote of 1.4 and a homozygote of 1.96. Lax ton and so on again based on the study shows that homozygous genotype of the population is more prone to coronary artery disease.
Suzuki and other experiments to exclude gender, age, body mass index, hemoglobin concentration, through case-control studies to prove that lymphotoxin α252 gene mutation and high-sensitivity C-reactive protein, C-reactive protein levels not only with the cause of malignant inflammation of environmental factors And is associated with lymphotoxin alpha gene polymorphism, C-reactive protein is one of the risk factors associated with cardiovascular disease.
In a large study of the relationship between lymphotoxin alpha and coronary heart disease in the German population, 1821 patients with positive myocardial infarction (1214 positive family history, 607 negative family history) and 2572 controls in the control group were selected. The results showed that the polymorphism of lymphotoxin α gene was not related to the occurrence and development of myocardial infarction. And Koch et al. Conducted a large-scale study of 3,657 patients with myocardial infarction and 1211 healthy subjects in Germany. The study sites included lymphotoxin alpha G162A (rs1800683), A252G (rs909253), rs1041981 and T26N (Thr26Asn) It is shown that lymphotoxin α is a protective factor in the pathogenesis of myocardial infarction.
Clarke et al. Conducted the largest study on the relationship between lymphotoxin alpha gene polymorphism and myocardial infarction, including 6928 patients with myocardial infarction and 2712 controls. The study sites included rs2071590, rs1800683, rs909253, rs746868, Rs2857713, rs3093543 and rs1041981. The results showed that there was no correlation between the polymorphism of lymphotoxin alpha and the susceptibility to coronary heart disease.
Summary and prospect of lymphotoxin
Inflammation plays an important role in the pathogenesis of vascular disease. Genetic studies have shown that lymphotoxin alpha gene variation affects its expression and biological function, thereby increasing the risk of coronary heart disease and myocardial infarction. In vitro experiments have shown that galactinol 2 inhibition will reduce or inhibit the expression of lymphotoxin alpha. The lack of lymphotoxin in rats can cause large atherosclerotic plaque reduction. However, at the same time a large number of clinical trials have shown that there is no correlation between lymphotoxin alpha gene polymorphism and the incidence of coronary heart disease. Whether LT-α plays an important role in the pathogenesis and pathogenesis of coronary heart disease remains controversial.