C-C chemokine receptor type 9 is a protein that in humans is encoded by the CCR9 gene. [5] [6] This gene is mapped to the chemokine receptor gene cluster region. Two alternatively spliced transcript variants have been described. [6]
CCR9 has also recently been designated CDw199 (cluster of differentiation w199).
The protein encoded by this gene is a member of the beta chemokine receptor family. CCR9 is a seven transmembrane protein similar to G protein-coupled receptors. [7] [8] [9]
Chemokines and their receptors, such as CCR9 and its binding agonist, are key regulators of thymocyte migration and maturation in normal and inflammatory conditions. [8] The specific agonist or ligand that binds CCR9 is CCL25 also referred to as TECK [10] in some literature. The effects of chemokines binding to their specific receptors is generally dependent on the structural placement of the N terminal cysteine(s) amino acids. [11] Receptors are broken down into 4 family groups CXC, CC, C, and CX3C, because CCR9 has two adjacent cysteines it is a C-C family receptor. [11] C-C family chemokines (such as CCL25) are often associated with the recruitment of lymphocytes. [11] [8] It has been found that this gene is differentially expressed by T lymphocytes of small intestine and colon, suggesting a role in thymocyte recruitment and development that may permit functional specialization of immune responses in different segments of the gastrointestinal tract.
The breadth of effects following interactions of CCR9 and its binding ligand CCL25 are vast and not completely understood, however, it is generally thought that CCR9 and CCL25 play substantial roles in cancer proliferation and inflammatory diseases. [11] The location of CCR9 and CCL25 expression plays a substantial role in how it contributes to diseases. [11] For example, the high expression of CCL25 in the epithelial lining of the small intestine, has contributed to its strong association and influence on inflammatory disease of the gut such as inflammatory bowel disease. [11] However, CCR9 and CCL25 have also been associated with other inflammatory conditions such as cardiovascular disease, rheumatoid arthritis, and asthma. [11] [12] The role of CCR9 in cancer lies primarily in its ability to upregulate cell proliferation, metastasis, and the drug resistance. [12]
CCR9/CCL25 interactions are known to contribute to the up-regulated migration of memory T cell homing to the gut given high expression of CCL25 in intestinal lining. [11] As a result, it is suggested that CCR9 and CCL25 have been a key focus in promoting a balanced pro-inflammatory and anti-inflammatory response in the gut. [11] It has been observed that decreased expression of CCL25 and CCR9 contributes to macrophage recruitment in the gut as well as inflammatory cytokines which induces the observed inflammation in IBD. [11] The inflammatory cytokines upregulated in the immune response of IBD are TNF-α, IFN-γ, IL-2, IL-6, IL-17A, and Th1/Th17. [11] Overall, it is likely that the interactions of CCR9 and CCL25 provide substantial protections against large intestinal inflammation via its ability to regulate inflammation in the gut by balancing the presence of inflammatory cytokines. [11]
CCR9/CCL25 interaction reduction is believed to improve the survival rate, cardiac function, and reduce infarct size following myocardial infarctions. [11] Additionally, reduced CCR9 expression following myocardial infarctions is also believed to attenuate apoptosis in the cells of the affected cardiac tissue while also reducing inflammation through the down-regulation of inflammatory cytokines including: IL-1β, IL-6, and TNF-α. [11] Overall, CCR9 and CCL25 are believed to play a key role in mitigating the damage to cardiac tissue following heart attacks, while also aiding cardiac remodeling. [11] The role CCR9 and CCL25 is thought to have in cardiovascular health has made it a key area of focus in clinical research. [11]
CCR9/CCL25 interaction is believed to significantly influence the cellular functions of cancer cells and ultimately contribute to their proliferation and metastasis. [12] CCR9 and CCL25 interactions are understood to suppress apoptosis observed by cancer cells. [12] Apoptosis in cancer cells is an essential mechanism utilized to mitigate the proliferation of cancer cells. [12] The suggested reduction in apoptosis observed in cancer cells as a result of CCR9 and CCL25 interactions, ultimately supports the proliferation and metastasis of cancer cells. [12] The observed proliferative and antiapoptotic effects of CCR9/CCL25 interaction, suggests the potential for targeted therapies that down-regulate CCR9/CCL25 for certain cancers including: leukemia, prostate cancer, breast cancer, ovarian cancer and lung cancer. [12]
Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.
Chemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. The gene has been discovered in 1990 by in situ hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTES. RANTES was first described by Dr. Tom Schall who named the protein, the original source of the name Rantes was from the Argentine movie Man Facing Southeast about an alien who shows up in a mental ward who was named Rantés, the rather clunky acronym was only made to fit the name.
Chemokine ligand 28 (CCL28), also known as mucosae-associated epithelial chemokine (MEC), CCK1 and SCYA28, is a chemokine. CCL28 regulates the chemotaxis of cells that express the chemokine receptors CCR3 and CCR10. CCL28 is expressed by columnar epithelial cells in the gut, lung, breast and the salivary glands and drives the mucosal homing of T and B lymphocytes that express CCR10, and the migration of eosinophils expressing CCR3. This chemokine is constitutively expressed in the colon, but its levels can be increased by pro-inflammatory cytokines and certain bacterial products implying a role in effector cell recruitment to sites of epithelial injury. CCL28 has also been implicated in the migration of IgA-expressing cells to the mammary gland, salivary gland, intestine and other mucosal tissues. It has also been shown as a potential antimicrobial agent effective against certain pathogens, such as Gram negative and Gram positive bacteria and the fungus Candida albicans.
Chemokine ligands 4 previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the CCL4 gene. CCL4 belongs to a cluster of genes located on 17q11-q21 of the chromosomal region. Identification and localization of the gene on the chromosome 17 was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxin-stimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties.
Chemokine ligand 1 (CCL1) is also known as small inducible cytokine A1 and I-309 in humans. CCL1 is a small glycoprotein that belongs to the CC chemokine family.
Chemokine ligand 7 (CCL7) is a small cytokine that was previously called monocyte-chemotactic protein 3 (MCP3). CCL7 is a small protein that belongs to the CC chemokine family and is most closely related to CCL2.
Chemokine ligand 20 (CCL20) or liver activation regulated chemokine (LARC) or Macrophage Inflammatory Protein-3 (MIP3A) is a small cytokine belonging to the CC chemokine family. It is strongly chemotactic for lymphocytes and weakly attracts neutrophils. CCL20 is implicated in the formation and function of mucosal lymphoid tissues via chemoattraction of lymphocytes and dendritic cells towards the epithelial cells surrounding these tissues. CCL20 elicits its effects on its target cells by binding and activating the chemokine receptor CCR6.
Chemokine ligand 18 (CCL18) is a small cytokine belonging to the CC chemokine family. The functions of CCL18 have been well studied in laboratory settings, however the physiological effects of the molecule in living organisms have been difficult to characterize because there is no similar protein in rodents that can be studied. The receptor for CCL18 has been identified in humans only recently, which will help scientists understand the molecule's role in the body.
Chemokine ligand 16 (CCL16) is a small cytokine belonging to the CC chemokine family that is known under several pseudonyms, including Liver-expressed chemokine (LEC) and Monotactin-1 (MTN-1). This chemokine is expressed by the liver, thymus, and spleen and is chemoattractive for monocytes and lymphocytes. Cellular expression of CCL16 can be strongly induced in monocytes by IL-10, IFN-γ and bacterial lipopolysaccharide. Its gene is located on chromosome 17, in humans, among a cluster of other CC chemokines. CCL16 elicits its effects on cells by interacting with cell surface chemokine receptors such as CCR1, CCR2, CCR5 and CCR8.
Chemokine ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine, exodus-2, and secondary lymphoid-tissue chemokine (SLC). The gene for CCL21 is located on human chromosome 9. CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7.
C-C motif chemokine 22 is a protein that in humans is encoded by the CCL22 gene.
CCL17 is a powerful chemokine produced in the thymus and by antigen-presenting cells like dendritic cells, macrophages, and monocytes. CCL17 plays a complex role in cancer. It attracts T-regulatory cells allowing for some cancers to evade an immune response. However, in other cancers, such as melanoma, an increase in CCL17 is linked to an improved outcome. CCL17 has also been linked to autoimmune and allergic diseases.
Chemokine ligand 19 (CCL19) is a protein that in humans is encoded by the CCL19 gene.
CC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. To date, ten true members of the CC chemokine receptor subfamily have been described. These are named CCR1 to CCR10 according to the IUIS/WHO Subcommittee on Chemokine Nomenclature.
C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21).
Chemokine receptor 6 also known as CCR6 is a CC chemokine receptor protein which in humans is encoded by the CCR6 gene. CCR6 has also recently been designated CD196. The gene is located on the long arm of Chromosome 6 (6q27) on the Watson (plus) strand. It is 139,737 bases long and encodes a protein of 374 amino acids.
C-C chemokine receptor type 10 is a protein that in humans is encoded by the CCR10 gene.
Chemokine-binding protein 2 is a protein that in humans is encoded by the CCBP2 gene.
Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.
C-C motif chemokine ligand 27 is a protein that in humans is encoded by the CCL27 gene.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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