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]
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 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 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). CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7. The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.
Chemokine ligand 19 (CCL19) is a protein that in humans is encoded by the CCL19 gene.
Chemokine ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as monokine induced by gamma interferon (MIG). The CXCL9 is one of the chemokine which plays role to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation.
CX3C motif chemokine receptor 1 (CX3CR1), also known as the fractalkine receptor or G-protein coupled receptor 13 (GPR13), is a transmembrane protein of the G protein-coupled receptor 1 (GPCR1) family and the only known member of the CX3C chemokine receptor subfamily.
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.
Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. It has been shown to be involved in the onset of many diseases, including Inflammatory bowel disease due to the high expression of TLR in intestinal lamina propria dendritic cells. Recent studies have also shown that malfunctioning of TLR5 is likely related to rheumatoid arthritis, osteoclastogenesis, and bone loss. Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.
Tyrosine-protein kinase JAK3 is a tyrosine kinase enzyme that in humans is encoded by the JAK3 gene.
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). The ligands have similar affinity for the receptor, though CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals. CCR7 is a transmembrane protein with 7 transmembrane domains, which is coupled with heterotrimeric G proteins, which transduce the signal downstream through various signalling cascades. The main function of the receptor is to guide immune cells to immune organs by detecting specific chemokines, which these tissues secrete.
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.
Signaling lymphocytic activation molecule 1 is a protein that in humans is encoded by the SLAMF1 gene. Recently SLAMF1 has also been designated CD150.
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.
Gut-specific homing is the mechanism by which activated T cells and antibody-secreting cells (ASCs) are targeted to both inflamed and non-inflamed regions of the gut in order to provide an effective immune response. This process relies on the key interaction between the integrin α4β7 and the addressin MadCAM-1 on the surfaces of the appropriate cells. Additionally, this interaction is strengthened by the presence of CCR9, a chemokine receptor, which interacts with TECK. Vitamin A-derived retinoic acid regulates the expression of these cell surface proteins.
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.
