View source for Chemokine



[[Image:IL8 Solution Structure.rsh.png|thumb|300px|right|Solution structure of [[interleukin-8]], a chemokine of the CXC subfamily]]

'''Chemokines''' are a family of small [[cytokines]], or [[protein]]s secreted by [[Cell (biology)|cell]]s. Proteins are classified as chemokines according to shared structural characteristics such as small size (they are all approximately 8-10 [[kilodalton]]s in size), and the presence of four [[cysteine]] residues in conserved locations that are key to forming their 3-dimensional shape.  Their name is derived from their ability to induce directed [[chemotaxis]] in nearby responsive cells; they are '''chemo'''tactic cyto'''kines'''. However, 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 [[inflammation|pro-inflammatory]] and can be induced during an immune response to promote 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 [[developmental biology|development]].  Chemokines are found in all [[vertebrate]]s, some [[virus]]es and some [[bacteria]], but none have been described for other [[invertebrate]]s.  These proteins exert their biological effects by interacting with [[G protein]]-linked [[transmembrane receptor]]s called [[chemokine receptor]]s, that are selectively found on the surfaces of their target cells.

==Function==
[[Image:Chemokine_concentration_chemotaxis.jpg|thumb|right|300px|Chemokines released by infected or damaged cells form a concentration gradient.  Attracted cells move through the gradient towards the higher concentration of chemokine.]]
The major role of chemokines is 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 [[lymphocyte]]s to the [[lymph node]]s so they can screen for invasion of pathogens by interacting with [[antigen-presenting cell]]s residing in these tissues.  These are known as [[homeostatic]] chemokines and are produced and secreted without any need to stimulate their source cell(s).  Some chemokines have roles in development; they promote [[angiogenesis]] (the growth of new [[blood vessel]]s), 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 [[bacteria]]l infection, [[virus]]es and agents that cause physical damage such as [[silica]] or the [[Uric acid|urate crystal]]s that occur in [[gout]]. Their release is often stimulated by pro-inflammatory cytokines such as [[interleukin 1]].  Inflammatory chemokines function mainly as chemoattractants for [[leukocyte]]s, recruiting [[monocyte]]s, [[neutrophil]]s 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]].

==Structural characteristics==
[[Image:ChtxChemkinStr2.png|300px|right|thumb|All chemokines share a typical ''[[Greek key]]'' structure that is stabilised by [[disulphide bond]]s between conserved [[cysteine]] residues.]]
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]]. They are approximately 20-50% identical to each other; that is, they share [[gene]] [[Primary structure|sequence]] and [[amino acid]] [[Primary structure|sequence]] homology. They all also possess conserved [[amino acid]]s that are important for creating their 3-dimensional or [[tertiary structure]], such as (in most cases) four [[cysteine]]s that interact with each other in pairs to create a [[Greek key]] shape that is a characteristic of chemokines. Intramolecular [[disulphide bond]]s 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 [[Protein precursor|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 [[3 10 helix|3<sub>10</sub>-helix]], three [[beta strand|β-strands]] and a C-terminal [[Alpha helix|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.<ref>{{cite journal |author=Fernandez E, Lolis E |title=Structure, function, and inhibition of chemokines |journal=Annu Rev Pharmacol Toxicol |volume=42 |issue= |pages=469-99 |year= |id=PMID 11807180}}</ref>

==Types==

{| border="1" align="right" style="margin: 10px; border:3px; color: #8888aa" width = 355px; font: small
|-
| colspan="4" style="text-align: center;" | [[Image:ChtxChemokineStruct.png|300px|The four chemokine subfamilies]]
|-
| colspan="4"  align="center" style="color: blue; background: #ccccff" | '''CC chemokines''' 
|-align="left" style="color: black; background: #ccccff" |
| <small>'''Name''' ||<small> '''Gene''' ||<small> '''Other name(s)''' || <small>'''Uniprot'''</small>
|-
| <small>[[CCL1]] || <small>Scya1 || <small>I-309, TCA-3|| <small>P22362
|-
| <small>[[CCL2]] || <small>Scya2 || <small>MCP-1 || <small>P13500
|-
| <small>[[CCL3]] || <small>Scya3 ||<small> MIP-1α||<small> P10147
|-
|<small> [[CCL4]] ||<small> Scya4 ||<small> MIP-1β||<small> P13236
|-
|<small> [[CCL5]] ||<small> Scya5 ||<small> RANTES ||<small> P13501
|-
| <small>[[CCL6]] ||<small> Scya6 ||<small> C10, MRP-2||<small> P27784
|-
|<small> [[CCL7]] ||<small> Scya7 ||<small> MARC, MCP-3||<small> P80098
|-
|<small> [[CCL8]] ||<small> Scya8 ||<small> MCP-2||<small> P80075
|-
| <small>[[CCL9]]/[[CCL10]]||<small> Scya9 ||<small> MRP-2, CCF18, MIP-1γ ||<small> P51670
|-
|<small> [[CCL11]] ||<small> Scya11 ||<small> Eotaxin ||<small> P51671
|-
|<small> [[CCL12]] ||<small> Scya12 ||<small> MCP-5||<small> Q62401
|-
|<small> [[CCL13]] ||<small> Scya13 ||<small> MCP-4, NCC-1, Ckβ10||<small> Q99616
|-
|<small> [[CCL14]] ||<small> Scya14 ||<small> HCC-1, MCIF, Ckβ1, NCC-2, CCL  ||<small> Q16627
|-
|<small> [[CCL15]] ||<small> Scya15 ||<small> Leukotactin-1, MIP-5, HCC-2, NCC-3 ||<small> Q16663
|-
|<small> [[CCL16]] ||<small> Scya16 ||<small> LEC, NCC-4, LMC, Ckβ12 || <small>O15467
|-
|<small> [[CCL17]] ||<small> Scya17 ||<small> TARC, dendrokine, ABCD-2 ||<small> Q92583
|-
|<small> [[CCL18]] ||<small> Scya18 ||<small> PARC, DC-CK1, AMAC-1, Ckβ7, MIP-4 ||<small> P55774
|-
|<small> [[CCL19]] ||<small> Scya19 ||<small> ELC, Exodus-3, Ckβ11 ||<small> Q99731
|-
|<small> [[CCL20]] ||<small> Scya20 ||<small> LARC, Exodus-1, Ckβ4 ||<small> P78556
|-
|<small> [[CCL21]] ||<small> Scya21 ||<small> SLC, 6Ckine, Exodus-2, Ckβ9, TCA-4 ||<small> O00585
|-
|<small> [[CCL22]] ||<small> Scya22 ||<small> MDC, DC/β-CK ||<small> O00626
|-
|<small> [[CCL23]] ||<small> Scya23 ||<small> MPIF-1, Ckβ8, MIP-3, MPIF-1 ||<small> P55773
|-
|<small> [[CCL24]] ||<small> Scya24 ||<small> Eotaxin-2, MPIF-2, Ckβ6||<small> O00175
|-
|<small> [[CCL25]] ||<small> Scya25 ||<small> TECK, Ckβ15 ||<small> O15444
|-
|<small> [[CCL26]] ||<small> Scya26 ||<small> Eotaxin-3, MIP-4α, IMAC, TSC-1||<small> Q9Y258
|-
|<small> [[CCL27]] ||<small> Scya27 ||<small> CTACK, ILC, Eskine, PESKY, skinkine ||<small> Q9Y4X3
|-
|<small> [[CCL28]] ||<small> Scya28 ||<small> MEC ||<small> Q9NRJ3
|-
| colspan="4" align="center" style="color: blue; background: #ccccff" | '''CXC chemokines''' 
|-align="left" style="color: black; background: #ccccff" |
|<small> '''Name''' ||<small> '''Gene''' ||<small> '''Other name(s)''' ||<small> '''Uniprot'''
|-
|<small> [[CXCL1]] ||<small> Scyb1 ||<small> Gro-α, GRO1, NAP-3 ||<small> P09341
|-
|<small> [[CXCL2]] ||<small> Scyb2 ||<small> Gro-β, GRO2, MIP-2α ||<small> P19875
|-
|<small> [[CXCL3]] ||<small> Scyb3 ||<small> Gro-γ, GRO3, MIP-2β ||<small> P19876
|-
|<small> [[CXCL4]] ||<small> Scyb4 ||<small> PF-4 ||<small> P02776
|-
|<small> [[CXCL5]] ||<small> Scyb5 ||<small> ENA-78 ||<small> P42830
|-
|<small> [[CXCL6]] ||<small> Scyb6 ||<small> GCP-2 ||<small> P80162
|-
|<small> [[CXCL7]] ||<small> Scyb7 ||<small> NAP-2, CTAPIII, β-Ta, PEP ||<small> P02775
|-
|<small> [[interleukin 8|CXCL8]] ||<small> Scyb8 ||<small> IL-8, NAP-1, MDNCF, GCP-1 ||<small> P10145
|-
|<small> [[CXCL9]] ||<small> Scyb9 ||<small> MIG, CRG-10 ||<small> Q07325
|-
|<small> [[CXCL10]] ||<small> Scyb10 ||<small> IP-10, CRG-2 ||<small> P02778
|-
|<small> [[CXCL11]] ||<small> Scyb11 ||<small> I-TAC, β-R1, IP-9 ||<small> O14625
|-
|<small> [[CXCL12]] ||<small> Scyb12 ||<small> SDF-1, PBSF ||<small> P48061
|-
|<small> [[CXCL13]] ||<small> Scyb13 ||<small> BCA-1, BLC ||<small> O43927
|-
|<small> [[CXCL14]] ||<small> Scyb14 ||<small> BRAK, bolekine ||<small> O95715
|-
|<small> [[CXCL15]] ||<small> Scyb15 ||<small> Lungkine, WECHE ||<small> Q9WVL7
|-
|<small> [[CXCL16]] ||<small> Scyb16 ||<small> SRPSOX ||<small> Q9H2A7
|-
|<small> [[CXCL17]] ||<small> VCC-1 ||<small> DMC, VCC-1 ||<small> Q6UXB2
|-
| colspan="4" align="center" style="color: blue; background: #ccccff" |'''C chemokines'''
|-align="left" style="color: black; background: #ccccff" |
|<small> '''Name''' ||<small> '''Gene''' ||<small> '''Other name(s)''' ||<small> '''Uniprot'''
|-
|<small> [[XCL1]] ||<small> Scyc1 ||<small>  Lymphotactin α, SCM-1α, ATAC ||<small> P47992
|-
|<small> [[XCL2]] ||<small> Scyc2 ||<small> Lymphotactin β, SCM-1β ||<small> Q9UBD3
|-
| colspan="4" align="center" style="color: blue; background: #ccccff" | '''CX3C chemokines''' 
|-align="left" style="color: black; background: #ccccff" |
|<small> '''Name''' ||<small> '''Gene''' || <small>'''Other name(s)''' ||<small> '''Uniprot'''
|-
|<small> [[CX3CL1]] ||<small> Scyd1 ||<small> Fractalkine, Neurotactin, ABCD-3 ||<small> P78423
|}

Members of the chemokine family are categorized into four groups depending on the spacing of their first two cysteine residues. 

===CC chemokines===
The CC chemokines (or β-chemokines) have two adjacent cysteines 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.<ref>{{cite journal |author=Laing K, Secombes C |title=Chemokines |journal=Dev Comp Immunol |volume=28 |issue=5 |pages=443-60 |year=2004 |id=PMID 15062643}}</ref> CC chemokines induce the migration of [[monocyte]]s and other cell types such as [[NK cells]] and [[dendritic cells]]. An example of a CC chemokine is [[CCL2|monocyte chemoattractant protein-1]] (MCP-1 or CCL2) which induces monocytes to leave the bloodstream and enter the surrounding tissue to become tissue [[macrophage]]s.  
CC chemokines induce cellular migration by binding to and activating [[CC chemokine receptors]], ten of which have been discovered to date and called CCR1-10. These receptors are expressed on the surface of different cell types allowing their specific attraction by the chemokines. A CC chemokine that attracts lymphocytes is [[CCL28]], which is chemoattractant to [[T cell]]s and [[B cell]]s that express the [[chemokine receptor]] [[CC chemokine receptors#CCR10|CCR10]]. This chemokine can also attract [[eosinophil]]s that express [[CC chemokine receptors#CCR3|CCR3]].  CCL5 (or [[RANTES]]) attracts cells such as T cells, eosinophils and [[basophil]]s that express the receptor [[CC chemokine receptors#CCR5|CCR5]].  

===CXC chemokines===
The two N-terminal cysteines of CXC chemokines (or α-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) of [[Glutamic 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 of [[neutrophil]]s, and interact with chemokine receptors [[CXC chemokine receptors#CXCR1 and CXCR2|CXCR1 and CXCR2]]. An example of an ELR-positive CXC chemokine is [[interleukin-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 as [[CXCL13]], tend to be chemoattractant for lymphocytes. CXC chemokines bind to [[CXC chemokine receptors]], of which seven have been discovered to date, designated CXCR1-7. 

===C chemokines===
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).  These chemokines attract T cell precursors to the [[thymus]]. 

===CX<sub>3</sub>C chemokines===
A fourth group has also been discovered and members have three amino acids between the two cysteines and is termed CX<sub>3</sub>C chemokine (or δ-chemokines). The only CX<sub>3</sub>C chemokine discovered to date is called [[fractalkine]] (or CX<sub>3</sub>CL1). It is both secreted and tethered to the surface of the cell that expresses it, thereby serving as both a chemoattractant and as an [[adhesion molecule]].

==Receptors==
{{details|Chemokine receptor}}
===Structure and Features===
[[Chemokine receptor]]s are [[G protein-coupled receptor]]s containing 7 [[transmembrane helix|transmembrane domain]]s that are found on the surface of [[leukocyte]]s. Approximately 19 different chemokine receptors have been characterized to date, which are divided into four families depending on the type of chemokine they bind; [[CXC chemokine receptors|CXCR]] that bind CXC chemokines, [[CC chemokine receptors|CCR]] that bind CC chemokines, [[CX3CR1]] that binds the sole CX3C chemokine (CX3CL1), and [[XCR1]] that binds the two XC chemokines (XCL1 and XCL2).  They share many structural features; they are similar in size (with about 350 [[amino acid]]s), have a short, acidic N-terminal end, seven helical transmembrane domains with three [[intracellular]] and three [[extracellular]] [[hydrophilic]] loops, and an intracellular C-terminus containing [[serine]] and [[threonine]] residues important for receptor regulation. The first two extracellular loops of chemokine receptors each has a conserved [[cysteine]] residue that allow formation of a disulphide 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.<ref>{{cite journal | author=Craig Murdoch and Adam Finn | title=Chemokine receptors and the role in inflammation and infectious disease | journal= Journal of the American Society of Hematology | year=2000 | volume=95 |issue=10 | pages= 3032-3043}}</ref>

===Signal Transduction=== 
Chemokine receptors associate with G-proteins to transmit [[Cell signaling|cell signals]] following ligand binding. Activation of G proteins, by chemokine receptors, causes the subsequent activation of an [[enzyme]] known as [[phospholipase C]] (PLC). PLC cleaves a molecule called [[Phosphatidylinositol (4,5)-bisphosphate]] (PIP2) into two [[second messenger]] molecules known as [[Inositol triphosphate]] (IP3) and [[diglyceride|diacylglycerol]] (DAG) that trigger intracellular signaling events; DAG activates another enzyme called [[protein kinase C]] (PKC), and IP3 triggers the release of [[Calcium in biology|calcium]] from intracellular stores. These events promote many signaling cascades (such as the [[MAPK/ERK pathway|MAP kinase pathway]]) that generate responses like [[chemotaxis]], [[degranulation]], release of [[superoxide]] anions and changes in the avidity of [[cell adhesion molecule]]s called [[integrin]]s within the cell harbouring the chemokine receptor.<ref>{{cite journal | author=Craig Murdoch and Adam Finn | title=Chemokine receptors and the role in inflammation and infectious disease | journal= Journal of the American Society of Hematology | year=2000 | volume=95 |issue=10 | pages= 3032-3043}}</ref>

==Infection control==
The discovery that the &beta; chemokines [[RANTES]], MIP ([[Macrophage Inflammatory Protein]]s) 1&alpha; and 1&beta; (now known as CCL5, CCL3 and CCL4 respectively) suppress [[HIV|HIV-1]] provided the initial connection and indicated that these molecules might control infection as part of immune responses in vivo.<ref>{{cite journal | author=Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, [[Robert Gallo|Gallo RC]], and Lusso P | title= Identification of RANTES, MIP-1a, and MIP-1b as the major HIV-suppressive factor produced by CD8+ T cells | journal= Science | year=October 1995 | volume=270 | pages=1811-1815}}</ref> The association of chemokine production with antigen-induced proliferative responses, more favorable clinical status in [[HIV]] 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.<ref>{{cite journal | author=Alfredo Garzino-Demo, Ronald B. Moss, Joseph B. Margolick, Farley Cleghorn, Anne Sill, William A. Blattner, Fiorenza Cocchi, Dennis J. Carlo, Anthony L. DeVico, and [[Robert Gallo|Robert C. Gallo]] | title= [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=18399&rendertype=abstract Spontaneous and antigen-induced production of HIV-inhibitory &#946;-chemokines are associated with AIDS-free status] | journal= Proc Natl Acad Sci U S A | year=October 1999 | volume=96 |issue=21 | pages= 11986–11991}}</ref>

== External links ==
*[http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1280 IUPHAR GPCR Database - Chemokine Receptors]
*[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=imm.table.2501 List of chemokines and their receptors] at nlm.nih.gov
*[http://cytokine.medic.kumamoto-u.ac.jp/CFC/CK/Chemokine.html The cytokine family database - Chemokines] at kumamoto-u.ac.jp
*[http://www.rndsystems.com/chemokine_nomenclature.aspx  The correct chemokine nomenclature] at rndsystems.com

==See also==
* [[Paracrine signalling]]

==References==
<references/>


{{Cytokines}}
{{Chemokines}}

[[Category:Cytokines]]
[[Category:Signal transduction]]

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