CCL5

CCL5 belongs to the CC subfamily of chemokines, due to its adjacent cysteines near N terminus. It is an 8kDa protein acting as a classical chemotactic cytokine or chemokine. It consists of 68 amino acids. CCL5 is proinflammatory chemokine, recruiting leukocytes to the site of inflammation. It is chemotactic for T cells, eosinophils, and basophils, but also for monocytes, natural-killer (NK) cells, dendritic cells and mastocytes. With the help of particular cytokines (i.e., IL-2 and IFN-γ) that are released by T cells, CCL5 also induces the proliferation and activation of certain NK cells to form CHAK (CC-Chemokine-activated killer) cells. It is also an HIV-suppressive factor released from CD8+ T cells The chemokine CCL5 is mainly expressed by T-cells and monocytes, and it has not been shown to be expressed by B-cells. Moreover, it is abundantly expressed by epithelial cells, fibroblasts and thrombocytes. Although it can bind to receptors CCR1, CCR3, CCR4 and CCR5, belonging to seven transmembrane G-protein coupled receptor (GPCRs) family, The CCL5 gene is activated after 3–5 days after activation of T-cell via TCR. This is different from the most of other chemokines which are released almost immediately after cell stimulation. Thus, CCL5 is involved in inflammation maintaining. It also induces expression of matrix metalloproteinases which are important for migration of cells into the site of inflammation. Memory CD8+ T-cells are able to secrete CCL5 immediately after TCR stimulation, because they have a large number of preformed CCL5 mRNA in cytoplasm and its secretion is dependent only on translation. RANTES, along with the related chemokines MIP-1alpha and MIP-1beta, has been identified as a natural HIV-suppressive factor secreted by activated CD8+ T cells and other immune cells. == Interactions ==

CCL5 has been shown to interact with CCR3, CCR5 and CCR1. CCL5 has two mechanisms of action according to its concentration. • The first one occurs at low concentration of the chemokine. CCL5 may act as a monomer or a dimer. Dimerization is not necessary for binding to CCR5. Thus, CCL5 in nanomolar concentration acts as classical chemokine and binds to its receptor. For the acting as classical chemokine and for the dimerization, N terminus of the molecule is important. • The second one occurs at high concentration of the chemokine. CCL5 creates self-aggregates binding to glycosaminoglycans (GAGs) on the cell surface. For that, Glu66 and Glu26 are important. These amino acids are presented on the protein surface and allows ion interactions. In the experiment where these molecules were exchanged for serine, the self-aggregation did not occur. In vitro, the self-aggregates are strong activators of leukocytes. They can act as mitogens and they are not dependent on binding to the receptor. Activated T-cells (or other cells, for instance monocytes or neutrophils) either proliferate or perform apoptosis, and they release proinflammatory cytokines, such as IL-2, IL-5 and IFN-γ. == Clinical significance ==

CCL5 is involved in transplantations, and numerous human diseases and disorders, for instance viral hepatitis or COVID-19. Increased levels of CCL5 was discovered in lots of cancers. For instance in breast cancer, hepatocellular carcinoma, stomach cancer, prostate cancer and pancreatic cancer. CCL5 plays an important role in various human disorders, such as atherosclerosis, COVID-19, SARS, atopic dermatitis, asthma, glomerulonephritis, alcohol liver disease, acute liver failure and viral hepatitis. == See also ==