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.
Cytokine proteins are classified as chemokines according to behavior and structural characteristics. In addition to being known for mediating chemotaxis, chemokines are all approximately 8–10 kilodaltons in mass and have four cysteine residues in conserved locations that are key to forming their 3-dimensional shape.
These proteins have historically been known under several other names including the SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or intercrines. Some chemokines are considered pro-inflammatory and can be induced during an immune response to recruit cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development. Chemokines are found in all vertebrates, some viruses and some bacteria, but none have been found in other invertebrates.
Chemokines have been classified into four main subfamilies: CXC, CC, CX3C and C. All of these proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors, that are selectively found on the surfaces of their target cells.
Function
The major role of chemokines is to act as a chemoattractant to guide the migration of cells. Cells that are attracted by chemokines follow a signal of increasing chemokine concentration towards the source of the chemokine. Some chemokines control cells of the immune system during processes of immune surveillance, such as directing lymphocytes to the lymph nodes so they can screen for invasion of pathogens by interacting with antigen-presenting cells residing in these tissues. These are known as homeostatic chemokines and are produced and secreted without any need to stimulate their source cells. Some chemokines have roles in development; they promote angiogenesis (the growth of new blood vessels), or guide cells to tissues that provide specific signals critical for cellular maturation. Other chemokines are inflammatory and are released from a wide variety of cells in response to bacterial infection, viruses and agents that cause physical damage such as silica or the urate crystals that occur in gout. Their release is often stimulated by pro-inflammatory cytokines such as interleukin 1. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or tissue damage. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and serve to guide cells of both innate immune system and adaptive immune system.
Types by function Chemokines are functionally divided into two groups: Homeostatic: are constitutively produced in certain tissues and are responsible for basal leukocyte migration. These include: CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12 and CXCL13. This classification is not strict; for example, CCL20 can act also as pro-inflammatory chemokine. Inflammatory: these are formed under pathological conditions (on pro-inflammatory stimuli, such as IL-1, TNF-alpha, LPS, or viruses) and actively participate in the inflammatory response attracting immune cells to the site of inflammation. Examples are: CXCL-8, CCL2, CCL3, CCL4, CCL5, CCL11, CXCL10.
Homing
The main function of chemokines is to manage the migration of leukocytes (homing) in the respective anatomical locations in inflammatory and homeostatic processes.
Basal: homeostatic chemokines are basal produced in the thymus and lymphoid tissues. Their homeostatic function in homing is best exemplified by the chemokines CCL19 and CCL21 (expressed within lymph nodes and on lymphatic endothelial cells) and their receptor CCR7 (expressed on cells destined for homing in cells to these organs). Using these ligands is possible routing antigen-presenting cells (APC) to lymph nodes during the adaptive immune response. Among other homeostatic chemokine receptors include: CCR9, CCR10, and CXCR5, which are important as part of the cell addresses for tissue-specific homing of leukocytes. CCR9 supports the migration of leukocytes into the intestine, CCR10 to the skin and CXCR5 supports the migration of B-cell to follicles of lymph nodes. As well CXCL12 (SDF-1) constitutively produced in the bone marrow promotes proliferation of progenitor B cells in the bone marrow microenvironment.
Inflammatory: inflammatory chemokines are produced in high concentrations during infection or injury and determine the migration of inflammatory leukocytes into the damaged area. Typical inflammatory chemokines include: CCL2, CCL3 and CCL5, CXCL1, CXCL2 and CXCL8. A typical example is CXCL-8, which acts as a chemoattractant for neutrophils. In contrast to the homeostatic chemokine receptors, there is significant promiscuity (redundancy) associated with binding receptor and inflammatory chemokines. This often complicates research on receptor-specific therapeutics in this area.
Types by cell attracted
Monocytes / macrophages: the key chemokines that attract these cells to the site of inflammation include: CCL2, CCL3, CCL5, CCL7, CCL8, CCL13, CCL17 and CCL22. T-lymphocytes: the four key chemokines that are involved in the recruitment of T lymphocytes to the site of inflammation are: CCL2, CCL1, CCL22 and CCL17. Furthermore, CXCR3 expression by T-cells is induced following T-cell activation and activated T-cells are attracted to sites of inflammation where the IFN-y inducible chemokines CXCL9, CXCL10 and CXCL11 are secreted. Mast cells: on their surface express several receptors for chemokines: CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4. Ligands of these receptors CCL2 and CCL5 play an important role in mast cell recruitment and activation in the lung. There is also evidence that CXCL8 might be inhibitory of mast cells. Eosinophils: the migration of eosinophils into various tissues involved several chemokines of CC family: CCL11, CCL24, CCL26, CCL5, CCL7, CCL13, and CCL3. Chemokines CCL11 (eotaxin) and CCL5 (RANTES) acts through a specific receptor CCR3 on the surface of eosinophils, and eotaxin plays an essential role in the initial recruitment of eosinophils into the lesion. Neutrophils: are regulated primarily by CXC chemokines. An example CXCL8 (IL-8) is chemoattractant for neutrophils and also activating their metabolic and degranulation.
Structural characteristics
Proteins are classified into the chemokine family based on their structural characteristics, not just their ability to attract cells. All chemokines are small, with a molecular mass of between 8 and 10 kDa, optimally designed to ensure efficient communications. They are approximately 20-50% identical to each other; that is, they share gene sequence and amino acid sequence homology. They all also possess conserved amino acids that are important for creating their 3-dimensional or tertiary structure, such as (in most cases) four cysteines that interact with each other in pairs to create a Greek key shape that is a characteristic of chemokines. Intramolecular disulfide bonds typically join the first to third, and the second to fourth cysteine residues, numbered as they appear in the protein sequence of the chemokine. Typical chemokine proteins are produced as pro-peptides, beginning with a signal peptide of approximately 20 amino acids that gets cleaved from the active (mature) portion of the molecule during the process of its secretion from the cell. The first two cysteines, in a chemokine, are situated close together near the N-terminal end of the mature protein, with the third cysteine residing in the centre of the molecule and the fourth close to the C-terminal end. A loop of approximately ten amino acids follows the first two cysteines and is known as the N-loop. This is followed by a single-turn helix, called a 310-helix, three β-strands and a C-terminal α-helix. These helices and strands are connected by turns called 30s, 40s and 50s loops; the third and fourth cysteines are located in the 30s and 50s loops.
Types by structure CC chemokines Name Gene Other name(s) Receptor Uniprot CCL1 Scya1 I-309, TCA-3 CCR8 CCL2 Scya2 MCP-1 CCR2 P13500 CCL3 Scya3 MIP-1a CCR1, CCR5 P10147 CCL4 Scya4 MIP-1β CCR1, CCR5 P13236 CCL5 Scya5 RANTES CCR5 P13501 CCL6 Scya6 C10, MRP-2 CCR1 P27784 CCL7 Scya7 MARC, MCP-3 CCR2 P80098 CCL8 Scya8 MCP-2 CCR1, CCR2, CCR5 P80075 CCL9/CCL10 Scya9 MRP-2, CCF18, MIP-1? CCR1 P51670 CCL11 Scya11 Eotaxin CCR2, CCR3, CCR5 P51671 CCL12 Scya12 MCP-5 Q62401 CCL13 Scya13 MCP-4, NCC-1, Ckβ10 CCR2, CCR3, CCR5 Q99616 CCL14 Scya14 HCC-1, MCIF, Ckβ1, NCC-2, CCL CCR1 Q16627 CCL15 Scya15 Leukotactin-1, MIP-5, HCC-2, NCC-3 CCR1, CCR3 Q16663 CCL16 Scya16 LEC, NCC-4, LMC, Ckβ12 CCR1, CCR2, CCR5, CCR8 O15467 CCL17 Scya17 TARC, dendrokine, ABCD-2 CCR4 Q92583 CCL18 Scya18 PARC, DC-CK1, AMAC-1, Ckβ7, MIP-4 P55774 CCL19 Scya19 ELC, Exodus-3, Ckβ11 CCR7 Q99731 CCL20 Scya20 LARC, Exodus-1, Ckβ4 CCR6 P78556 CCL21 Scya21 SLC, 6Ckine, Exodus-2, Ckβ9, TCA-4 CCR7 O00585 CCL22 Scya22 MDC, DC/β-CK CCR4 O00626 CCL23 Scya23 MPIF-1, Ckβ8, MIP-3, MPIF-1 CCR1 P55773 CCL24 Scya24 Eotaxin-2, MPIF-2, Ckβ6 CCR3 O00175 CCL25 Scya25 TECK, Ckβ15 CCR9 O15444 CCL26 Scya26 Eotaxin-3, MIP-4a, IMAC, TSC-1 CCR3 Q9Y258 CCL27 Scya27 CTACK, ILC, Eskine, PESKY, skinkine CCR10 Q9Y4X3 CCL28 Scya28 MEC CCR3, CCR10 Q9NRJ3 CXC chemokines Name Gene Other name(s) Receptor Uniprot CXCL1 Scyb1 Gro-a, GRO1, NAP-3, KC CXCR2 P09341 CXCL2 Scyb2 Gro-β, GRO2, MIP-2a CXCR2 P19875 CXCL3 Scyb3 Gro-?, GRO3, MIP-2β CXCR2 P19876 CXCL4 Scyb4 PF-4 CXCR3B P02776 CXCL5 Scyb5 ENA-78 CXCR2 P42830 CXCL6 Scyb6 GCP-2 CXCR1, CXCR2 P80162 CXCL7 Scyb7 NAP-2, CTAPIII, β-Ta, PEP P02775 CXCL8 Scyb8 IL-8, NAP-1, MDNCF, GCP-1 CXCR1, CXCR2 P10145 CXCL9 Scyb9 MIG, CRG-10 CXCR3 Q07325 CXCL10 Scyb10 IP-10, CRG-2 CXCR3 P02778 CXCL11 Scyb11 I-TAC, β-R1, IP-9 CXCR3, CXCR7 O14625 CXCL12 Scyb12 SDF-1, PBSF CXCR4, CXCR7 P48061 CXCL13 Scyb13 BCA-1, BLC CXCR5 O43927 CXCL14 Scyb14 BRAK, bolekine O95715 CXCL15 Scyb15 Lungkine, WECHE Q9WVL7 CXCL16 Scyb16 SRPSOX CXCR6 Q9H2A7 CXCL17 VCC-1 DMC, VCC-1 Q6UXB2 C chemokines Name Gene Other name(s) Receptor Uniprot XCL1 Scyc1 Lymphotactin a, SCM-1a, ATAC XCR1 P47992 XCL2 Scyc2 Lymphotactin β, SCM-1β XCR1 Q9UBD3 CX3C chemokines Name Gene Other name(s) Receptor Uniprot CX3CL1 Scyd1 Fractalkine, Neurotactin, ABCD-3 CX3CR1 P78423
Members of the chemokine family are divided into four groups depending on the spacing of their first two cysteine residues. Thus the nomenclature for chemokines is, e.g.: CCL1 for the ligand 1 of the CC-family of chemokines, and CCR1 for its respective receptor.
CC chemokines The CC chemokine (or β-chemokine) proteins have two adjacent cysteines (amino acids), near their amino terminus. There have been at least 27 distinct members of this subgroup reported for mammals, called CC chemokine ligands (CCL)-1 to -28; CCL10 is the same as CCL9. Chemokines of this subfamily usually contain four cysteines (C4-CC chemokines), but a small number of CC chemokines possess six cysteines (C6-CC chemokines). C6-CC chemokines include CCL1, CCL15, CCL21, CCL23 and CCL28. CC chemokines induce the migration of monocytes and other cell types such as NK cells and dendritic cells.