| Small cytokines (intecrine/chemokine), interleukin-8 like | |||||||
|---|---|---|---|---|---|---|---|
 Solution structure ofinterleukin-8, a chemokine of the CXC subfamily | |||||||
| Identifiers | |||||||
| Symbol | IL8 | ||||||
| Pfam | PF00048 | ||||||
| InterPro | IPR001811 | ||||||
| PROSITE | PDOC00434 | ||||||
| SCOP2 | 3il8 /SCOPe /SUPFAM | ||||||
| |||||||
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Chemokines (from Ancient Greek χῠμείᾱ (khumeíā) 'alchemy' and κῑ́νησῐς (kī́nēsis) 'movement'), or chemotactic cytokines, are a family of smallcytokines orsignalingproteins secreted bycells that induce directional movement ofleukocytes, as well as other cell types, includingendothelial andepithelial cells.[1][2] In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, includingmorphogenesis and wound healing, as well as in thepathogenesis of diseases like cancers.[1][3]
Cytokine proteins are classified as chemokines according to behavior and structural characteristics. In addition to being known for mediatingchemotaxis, chemokines are all approximately 8–10kilodaltons in mass and have fourcysteine residues in conserved locations that are key to forming their 3-dimensional shape.
These proteins have historically been known under several other names including theSIS family of cytokines,SIG family of cytokines,SCY family of cytokines,Platelet factor-4 superfamily orintercrines. Some chemokines are considered pro-inflammatory and can be induced during an immune response to recruit cells of theimmune system to a site ofinfection, while others are consideredhomeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance ordevelopment. Chemokines are found in allvertebrates, someviruses and somebacteria, but none have been found in otherinvertebrates.
Chemokines have been classified into four main subfamilies: CXC, CC, CX3C and C. All of these proteins exert their biological effects by interacting withG protein-linkedtransmembrane receptors calledchemokine receptors, that are selectively found on the surfaces of their target cells.[4]
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 theimmune system during processes of immune surveillance, such as directinglymphocytes to thelymph nodes so they can screen for invasion of pathogens by interacting withantigen-presenting cells residing in these tissues. These are known ashomeostatic chemokines and are produced and secreted without any need to stimulate their source cells. Some chemokines have roles in development; they promoteangiogenesis (the growth of newblood vessels), or guide cells to tissues that provide specific signals critical for cellular maturation. Other chemokines areinflammatory and are released from a wide variety of cells in response tobacterial infection,viruses and agents that cause physical damage such assilica or theurate crystals that occur ingout. Their release is often stimulated by pro-inflammatory cytokines such asinterleukin 1. Inflammatory chemokines function mainly as chemoattractants forleukocytes, recruitingmonocytes,neutrophils and other effector cells from theblood to sites ofinfection or tissue damage. Certain inflammatory chemokines activate cells to initiate an immune response or promotewound healing. They are released by many different cell types and serve to guide cells of bothinnate immune system andadaptive immune system.
Chemokines are functionally divided into two groups:[5]
The main function of chemokines is to manage the migration ofleukocytes (homing) in the respective anatomical locations in inflammatory andhomeostatic processes.
Basal: homeostatic chemokines are basal produced in thethymus and lymphoid tissues. Their homeostatic function in homing is best exemplified by the chemokines CCL19 and CCL21 (expressed withinlymph nodes and on lymphatic endothelial cells) and their receptor CCR7 (expressed on cells destined for homing in cells to these organs). Using theseligands is possible routingantigen-presenting cells (APC) to lymph nodes during the adaptive immune response. Among other homeostatic chemokinereceptors include: CCR9, CCR10, and CXCR5, which are important as part of the cell addresses for tissue-specific homing ofleukocytes. CCR9 supports the migration of leukocytes into theintestine, CCR10 to theskin and CXCR5 supports the migration ofB-cell to follicles oflymph nodes. As well CXCL12 (SDF-1) constitutively produced in thebone marrow promotes proliferation of progenitor B cells in the bone marrow microenvironment.[7][8]
Inflammatory:inflammatory chemokines are produced in high concentrations duringinfection or injury and determine the migration of inflammatory leukocytes into the damaged area. Typical inflammatory chemokines include: CCL2, CCL3 andCCL5, CXCL1, CXCL2 andCXCL8. 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.[8]
Proteins are classified into the chemokine family based on their structural characteristics, not just their ability to attract cells. All chemokines are small, with amolecular mass of between 8 and 10kDa, optimally designed to ensure efficient communications.[11] They are approximately 20-50% identical to each other; that is, they sharegenesequence andamino acidsequence homology. They all also possess conservedamino acids that are important for creating their 3-dimensional ortertiary structure, such as (in most cases) fourcysteines that interact with each other in pairs to create aGreek key shape that is a characteristic of chemokines. Intramoleculardisulfide 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 aspro-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 theN-terminal end of the mature protein, with the third cysteine residing in the centre of the molecule and the fourth close to theC-terminal end. A loop of approximately ten amino acids follows the first two cysteines and is known as theN-loop. This is followed by a single-turn helix, called a310-helix, threeβ-strands and a C-terminalα-helix. These helices and strands are connected by turns called30s,40s and50s loops; the third and fourth cysteines are located in the 30s and 50s loops.[12]
 | ||||
| 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.
The CC chemokine (orβ-chemokine) proteins have two adjacent cysteines (amino acids), near theiramino terminus. There have been at least 27 distinct members of this subgroup reported for mammals, called CC chemokineligands (CCL)-1 to -28; CCL10 is the same asCCL9. 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.[13] CC chemokines induce the migration ofmonocytes and other cell types such asNK cells anddendritic cells.
Examples of CC chemokine includemonocyte chemoattractant protein-1 (MCP-1 or CCL2) which induces monocytes to leave the bloodstream and enter the surrounding tissue to become tissuemacrophages.
CCL5 (orRANTES) attracts cells such as T cells, eosinophils andbasophils that express the receptorCCR5.
IncreasedCCL11 levels in blood plasma are associated withaging (and reducedneurogenesis) in mice and humans.[14]
The two N-terminal cysteines of CXC chemokines (orα-chemokines) are separated by one amino acid, represented in this name with an "X". There have been 17 different CXC chemokines described in mammals, that are subdivided into two categories, those with a specific amino acid sequence (or motif) ofglutamic acid-leucine-arginine (or ELR for short) immediately before the first cysteine of the CXC motif (ELR-positive), and those without an ELR motif (ELR-negative). ELR-positive CXC chemokines specifically induce the migration ofneutrophils, and interact with chemokine receptorsCXCR1 and CXCR2. An example of an ELR-positive CXC chemokine isinterleukin-8 (IL-8), which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR motif, such asCXCL13, tend to be chemoattractant for lymphocytes. CXC chemokines bind toCXC chemokine receptors, of which seven have been discovered to date, designated CXCR1-7.
The third group of chemokines is known as the C chemokines (or γ chemokines), and is unlike all other chemokines in that it has only two cysteines; one N-terminal cysteine and one cysteine downstream. Two chemokines have been described for this subgroup and are called XCL1 (lymphotactin-α) and XCL2 (lymphotactin-β).
A fourth group has also been discovered and members have three amino acids between the two cysteines and is termed CX3C chemokine (or d-chemokines). The only CX3C chemokine discovered to date is calledfractalkine (or CX3CL1). It is both secreted and tethered to the surface of the cell that expresses it, thereby serving as both a chemoattractant and as anadhesion molecule.
Chemokine receptors areG protein-coupled receptors containing 7transmembrane domains that are found on the surface ofleukocytes. Approximately 19 different chemokine receptors have been characterized to date, which are divided into four families depending on the type of chemokine they bind;CXCR that bind CXC chemokines,CCR that bind CC chemokines,CX3CR1 that binds the sole CX3C chemokine (CX3CL1), andXCR1 that binds the two XC chemokines (XCL1 and XCL2). They share many structural features; they are similar in size (with about 350amino acids), have a short, acidic N-terminal end, seven helical transmembrane domains with threeintracellular and threeextracellularhydrophilic loops, and an intracellular C-terminus containingserine andthreonine residues important for receptor regulation. The first two extracellular loops of chemokine receptors each has a conservedcysteine residue that allow formation of a disulfide bridge between these loops. G proteins are coupled to the C-terminal end of the chemokine receptor to allow intracellular signaling after receptor activation, while the N-terminal domain of the chemokine receptor determines ligand binding specificity.[15]
Chemokine receptors associate with G-proteins to transmitcell signals following ligand binding. Activation of G proteins, by chemokine receptors, causes the subsequent activation of anenzyme known asphospholipase C (PLC). PLC cleaves a molecule calledphosphatidylinositol (4,5)-bisphosphate (PIP2) into twosecond messenger molecules known asInositol triphosphate (IP3) anddiacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme calledprotein kinase C (PKC), and IP3 triggers the release ofcalcium from intracellular stores. These events promote many signaling cascades (such as theMAP kinase pathway) that generate responses likechemotaxis,degranulation, release ofsuperoxide anions and changes in the avidity ofcell adhesion molecules calledintegrins within the cell harbouring the chemokine receptor.[15]
The discovery that the β chemokinesRANTES, MIP (macrophage inflammatory proteins) 1α and 1β (now known as CCL5, CCL3 and CCL4 respectively) suppressHIV-1 provided the initial connection and indicated that these molecules might control infection as part of immune responses in vivo,[16] and that sustained delivery of such inhibitors have the capacity of long-term infection control.[17] The association of chemokine production with antigen-induced proliferative responses, more favorable clinical status inHIV infection, as well as with an uninfected status in subjects at risk for infection suggests a positive role for these molecules in controlling the natural course of HIV infection.[18]