Interleukin 8: Difference between revisions

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'''Interleukin 8''' ('''IL8''' or chemokine (C-X-C motif) ligand 8, '''CXCL8''') is a [[chemokine]] produced by [[macrophages]] and other cell types such as [[epithelial cells]], airway smooth muscle cells<ref name="pmid10873157">{{cite journal | vauthors = Hedges JC, Singer CA, Gerthoffer WT | title = Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes | journal = Am. J. Respir. Cell Mol. Biol. | volume = 23 | issue = 1 | pages = 86–94 | year = 2000 | pmid = 10873157 | doi = 10.1165/ajrcmb.23.1.4014 }}</ref> and endothelial cells.  [[Endothelial cells]] store IL-8 in their storage vesicles, the [[Weibel-Palade bodies]].<ref name="pmid9802987">{{cite journal | vauthors = Wolff B, Burns AR, Middleton J, Rot A | title = Endothelial cell "memory" of inflammatory stimulation: human venular endothelial cells store interleukin 8 in Weibel-Palade bodies | journal = J. Exp. Med. | volume = 188 | issue = 9 | pages = 1757–62 | year = 1998 | pmid = 9802987 | pmc = 2212526 | doi = 10.1084/jem.188.9.1757 }}</ref><ref name="pmid9802986">{{cite journal | vauthors = Utgaard JO, Jahnsen FL, Bakka A, Brandtzaeg P, Haraldsen G | title = Rapid secretion of prestored interleukin 8 from Weibel-Palade bodies of microvascular endothelial cells | journal = J. Exp. Med. | volume = 188 | issue = 9 | pages = 1751–6 | year = 1998 | pmid = 9802986 | pmc = 2212514 | doi = 10.1084/jem.188.9.1751 }}</ref>  In humans, the interleukin-8 [[protein]] is encoded by the ''CXCL8'' [[gene]].<ref name="pmid1967588">{{cite journal | vauthors = Modi WS, Dean M, Seuanez HN, Mukaida N, Matsushima K, O'Brien SJ | title = Monocyte-derived neutrophil chemotactic factor (MDNCF/IL-8) resides in a gene cluster along with several other members of the platelet factor 4 gene superfamily | journal = Hum. Genet. | volume = 84 | issue = 2 | pages = 185–7 | year = 1990 | pmid = 1967588 | doi = 10.1007/BF00208938 }}</ref> IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms.<ref name="Brat DJ 2005. pages 122-133">{{cite journal | author = Brat DJ, Bellail AC, Van Meir EG | year = 2005 | title = The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis | url = | journal = Neuro-oncology | volume = 7 | issue = 2| pages = 122–133 | doi=10.1215/s1152851704001061}}</ref> In culture, a 72 amino acid peptide is the major form secreted by macrophages.<ref name="Brat DJ 2005. pages 122-133"/>
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{{GNF_Protein_box
| image = IL8_Solution_Structure.rsh.png
| image_source = [[Protein Data Bank|PDB]] rendering based on 1IL8.
| Name = Interleukin 8
| HGNCid = 6025
| Symbol = IL8
| AltSymbols =; 3-10C; AMCF-I; CXCL8; GCP-1; GCP1; K60; LECT; LUCT; LYNAP; MDNCF; MONAP; NAF; NAP-1; NAP1; SCYB8; TSG-1; b-ENAP
| OMIM = 146930
| ECnumber =
| Homologene = 47937
| MGIid =
| GeneAtlas_image1 = PBB_GE_IL8_211506_s_at.png
| GeneAtlas_image2 = PBB_GE_IL8_202859_x_at.png
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| Function = {{GNF_GO|id=GO:0005153 |text = interleukin-8 receptor binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008009 |text = chemokine activity}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}}  
| Process = {{GNF_GO|id=GO:0001525 |text = angiogenesis}} {{GNF_GO|id=GO:0006928 |text = cell motility}} {{GNF_GO|id=GO:0006935 |text = chemotaxis}} {{GNF_GO|id=GO:0006954 |text = inflammatory response}} {{GNF_GO|id=GO:0006955 |text = immune response}} {{GNF_GO|id=GO:0007050 |text = cell cycle arrest}} {{GNF_GO|id=GO:0007186 |text = G-protein coupled receptor protein signaling pathway}} {{GNF_GO|id=GO:0007242 |text = intracellular signaling cascade}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0019722 |text = calcium-mediated signaling}} {{GNF_GO|id=GO:0030155 |text = regulation of cell adhesion}} {{GNF_GO|id=GO:0030593 |text = neutrophil chemotaxis}} {{GNF_GO|id=GO:0042119 |text = neutrophil activation}} {{GNF_GO|id=GO:0045091 |text = regulation of retroviral genome replication}} {{GNF_GO|id=GO:0050930 |text = induction of positive chemotaxis}}  
  | Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 3576
    | Hs_Ensembl = ENSG00000169429
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{{SI}}


There are many receptors on the surface membrane capable of binding IL-8; the most frequently studied types are the [[G protein-coupled receptor|G protein-coupled]] serpentine receptors [[interleukin 8 receptor, alpha|CXCR1]] and [[interleukin 8 receptor, beta|CXCR2]]. Expression and affinity for IL-8 differs between the two receptors (CXCR1 > CXCR2). Through a chain of biochemical reactions, IL-8 is secreted and is an important mediator of the immune reaction in the innate immune system response.


'''Interleukin-8''' (IL-8) is a [[chemokine]] produced by [[macrophages]] and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the [[Weibel-Palade bodies]]<ref>Wolff B, Burns AR, Middleton J, Rot A. Endothelial cell "memory" of inflammatory stimulation: human venular endothelial cells store interleukin 8 in Weibel-Palade bodies. J Exp Med. 1998 Nov 2;188(9):1757-62. PMID 9802987</ref><ref>Utgaard JO, Jahnsen FL, Bakka A, Brandtzaeg P, Haraldsen G. Rapid secretion of prestored interleukin 8 from Weibel-Palade bodies of microvascular endothelial cells. J Exp Med. 1998 Nov 2;188(9):1751-6. PMID 9802986</ref>.  
== Function ==
IL-8, also known as ''neutrophil chemotactic factor'', has two primary functions.  It induces [[chemotaxis]] in target cells, primarily neutrophils but also other granulocytes, causing them to migrate toward the site of infection. IL-8 also induces phagocytosis once they have arrived.  IL-8 is also known to be a potent promoter of [[angiogenesis]]. In target cells, IL-8 induces a series of physiological responses required for migration and phagocytosis, such as increases in intracellular Ca<sup>2+</sup>, exocytosis (e.g. [[histamine]] release), and the [[respiratory burst]].


[[Toll-like receptor]]s are the receptors of the innate immune system. These receptors recognize antigen patterns (like LPS in gram negative bacteria). Through a chain of biochemical reactions IL-8 is secreted and is an important mediator of the immune reaction in the innate immune system response.
IL-8 can be secreted by any cells with [[toll-like receptor]]s that are involved in the innate immune response. Usually, it is the [[macrophages]] that see an antigen first, and thus are the first cells to release IL-8 to recruit other cells. Both monomer and [[homodimer]] forms of IL-8 have been reported to be potent inducers of the chemokine receptors CXCR1 and CXCR2.  The homodimer is more potent, but [[methylation]] of Leu25 can block the activity of homodimers.


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
IL-8 is believed to play a role in the pathogenesis of [[bronchiolitis]], a common respiratory tract disease caused by viral infection.{{citation needed|date=May 2017}}
{{PBB_Summary
| section_title =
| summary_text = The protein encoded by this gene is a member of the CXC chemokine family. This chemokine is one of the major mediators of the inflammatory response. This chemokine is secreted by several cell types. It functions as a chemoattractant, and is also a potent angiogenic factor. This gene is believed to play a role in the pathogenesis of bronchiolitis, a common respiratory tract disease caused by viral infection. This gene and other ten members of the CXC chemokine gene family form a chemokine gene cluster in a region mapped to chromosome 4q.<ref>{{cite web | title = Entrez Gene: IL8 interleukin 8| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3576| accessdate = }}</ref>
}}
It is also secreted in urinary tract infections.
==Function==
IL-8 can be secreted by any cells with [[toll-like receptor]]s which are involved in the innate immune response.  IL-8's primary function is to recruit [[neutrophils]] to phagocytose the antigen which trigger the antigen pattern [[toll-like receptors]].


When first encountering an [[antigen]], the primary cells to encounter it are the [[macrophages]] who [[phagocytose]] the particle.  Upon processing, they release [[chemokines]] to signal other immune cells to come in to the site of inflammation. IL-8 is one such chemokine. It serves as a chemical signal that attracts [[neutrophils]] at the site of [[inflammation]], and therefore is also known as Neutrophil Chemotactic Factor.
IL-8 is a member of the [[Chemokine#CXC chemokines|CXC chemokine family]]. The genes encoding this and the other ten members of the CXC chemokine family form a cluster in a region mapped to chromosome 4q.<ref name="pmid1967588"/><ref>{{cite web | title = Entrez Gene: IL8 interleukin 8| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3576| accessdate = }}</ref>


==Clinical significance==
== CXCL-8 mediated chemotaxis of the neutrophil ==
If a pregnant mother has high levels of interleukin-8, she has a higher [[Pathogenic theory of schizophrenia|risk of inducing]] [[schizophrenia]] in her offspring.<ref>Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, Perrin M, Gorman JM, Susser ES. Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. Am J Psychiatry. 2004 May;161(5):889-95. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15121655 Abstract] [http://ajp.psychiatryonline.org/cgi/content/full/161/5/889#SEC3 fulltext]</ref> High levels of Interleukin 8 have been shown to reduce the chance of good treatment responses to antipsychotic medication in schizophrenia.<ref>Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC. Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J Clin Psychiatry. 2004 Jul;65(7):940-7.</ref>
CXCL8 is the primary [[cytokine]] involved in the recruitment of [[neutrophils]] to the site of damage or infection; in a process called [[chemotaxis]]. A number of variables are essential for the successful chemotaxis of neutrophils, including the increased expression of high affinity adhesion molecules to secure the neutrophil to the endothelium near the affected site (and is therefore not washed away into the circulatory system), and that the neutrophil can digest its way through the basement membrane and the extracellular matrix (ECM) to reach affected site. CXCL8 plays a key role in inducing the cell signalling necessary to bring about these changes.<ref name="Dixit_2012">{{cite journal | vauthors = Dixit N, Simon SI | title = Chemokines, selectins and intracellular calcium flux: temporal and spatial cues for leukocyte arrest | journal = Frontiers in Immunology | volume = 3 | issue = | pages = 188 | year = 2012 | pmid = 22787461 | pmc = 3392659 | doi = 10.3389/fimmu.2012.00188 }}</ref>


Interleukin-8 is often associated with inflammation.
Firstly, at the site of infection [[histamine]] release causes vasodilation of the capillaries near the injured area which slows down the blood flow in the region and encourages leukocytes, such as neutrophils, to come closer to the endothelium, and away from the centre of the lumen where the rate of blood flow is highest. Once this occurs weak interactions are made between the [[selectins]] expressed on the neutrophil and endothelial cells (expression of which is also increased through the action of CXCL8 and other cytokines). On the neutrophil these are: L selectins, and on the endothelial cell: P and E selectins. This causes the "rolling" phase of chemotaxis.


==Nomenclature==
Once the neutrophil is rolling along the endothelium, it will come into contact with a CXCL8 molecule expressed on the surface which stimulates the cell signalling pathway, mediated through a G-coupled-protein-receptor. The binding of CXCL8 to CXCR1/2 on the neutrophil stimulates the neutrophils to upregulate their expression of the [[integrin]], LFA-1, which takes part in high affinity bonding with [[ICAM-1]] receptors expressed on the endothelium. The expression and affinity of LFA-1 is significantly increased to maximise binding. This causes the neutrophil to slow down more until it is stationary.
IL-8 was renamed CXCL8 by the Chemokine Nomenclature Subcommittee of the Nomenclature Committee of the International Union of Immunological Societies, although its approved gene symbol remains ''IL8''.
Another key function of the cell signalling stimulated by CXCL8, is the initiation of the oxidative burst. This process allows the build up of proteolytic enzymes and reactive oxygen species (ROS) which are necessary to break down the ECM and basement membrane. These are released in secretory granules, along with more integrins. The release of ROS and damaging enzymes is regulated to minimise host damage, but continues to reach site of infection at which it will carry out its effector functions.<ref name="Dixit_2012" />


==See also==
== Target cells ==
 
While neutrophil granulocytes are the primary target cells of IL-8, there are a relatively wide range of cells ([[endothelial cells]], [[macrophage]]s, [[mast cell]]s, and [[keratinocyte]]s) that respond to this chemokine. The chemoattractant activity of IL-8 in similar concentrations to vertebrates was proven in [[Tetrahymena]] pyriformis, which suggests a phylogenetically well-conserved structure and function for this chemokine.<ref name="pmid9702410">{{cite journal | vauthors = Köhidai L, Csaba G | title = Chemotaxis and chemotactic selection induced with cytokines (IL-8, RANTES and TNF-alpha) in the unicellular Tetrahymena pyriformis | journal = Cytokine | volume = 10 | issue = 7 | pages = 481–6 | year = 1998 | pmid = 9702410 | doi = 10.1006/cyto.1997.0328 }}</ref>
 
== Clinical significance ==
 
Interleukin-8 is a key mediator associated with inflammation where it plays a key role in neutrophil recruitment and neutrophil degranulation.<ref>{{cite journal | vauthors = Harada A, Sekido N, Akahoshi T, Wada T, Mukaida N, Matsushima K | title = Essential involvement of interleukin-8 (IL-8) in acute inflammation | journal = Journal of Leukocyte Biology | volume = 56 | issue = 5 | pages = 559–64 | date = Nov 1994 | pmid = 7964163 | url = http://www.jleukbio.org/content/56/5/559 }}</ref> As an example, it has been cited as a proinflammatory mediator in [[gingivitis]]<ref>Haake, SK, Huang, GTJ: Molecular Biology of the host-Microbe Interaction in Periodontal Diseases (Selected Topics). In Newman, Takei, Carranza, editors: ''Clinical Periodontology'', 9th Edition. Philadelphia: W.B.Saunders Co. 2002. page 162.</ref> and [[psoriasis]].
 
Interleukin-8 secretion is increased by oxidant stress, which thereby cause the recruitment of inflammatory cells and induces a further increase in oxidant stress mediators, making it a key parameter in localized inflammation.<ref name="pmid10477716">{{cite journal | vauthors = Vlahopoulos S, Boldogh I, Casola A, Brasier AR | title = Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation | journal = Blood | volume = 94 | issue = 6 | pages = 1878–89 | year = 1999 | pmid = 10477716 | doi =  }}</ref> IL-8 was shown to be associated with [[obesity]].<ref name="ImmunologicProfile">{{cite journal | vauthors = Sharabiani MT, Vermeulen R, Scoccianti C, Hosnijeh FS, Minelli L, Sacerdote C, Palli D, Krogh V, Tumino R, Chiodini P, Panico S, Vineis P | title = Immunologic profile of excessive body weight | journal = Biomarkers | volume = 16 | issue = 3 | pages = 243–51 | year = 2011 | pmid = 21506696 | doi = 10.3109/1354750X.2010.547948 }}</ref>
 
IL-8 has also been implied to have a role in colorectal cancer by acting as an [[autocrine]] growth factor for colon carcinoma cell lines<ref name="BrewErikson2000">{{cite journal | vauthors = Brew R, Erikson JS, West DC, Kinsella AR, Slavin J, Christmas SE | title = Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitro | journal = Cytokine | volume = 12 | issue = 1 | pages = 78–85 | year = 2000 | pmid = 10623446 | doi = 10.1006/cyto.1999.0518 }}</ref> or the promotion of division and possible migration by cleaving [[metalloproteinase]] molecules.<ref name="ItohJoh2005">{{cite journal | vauthors = Itoh Y, Joh T, Tanida S, Sasaki M, Kataoka H, Itoh K, Oshima T, Ogasawara N, Togawa S, Wada T, Kubota H, Mori Y, Ohara H, Nomura T, Higashiyama S, Itoh M | title = IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in human colon carcinoma cells | journal = Cytokine | volume = 29 | issue = 6 | year = 2005 | pmid = 15749028 | doi = 10.1016/j.cyto.2004.11.005 | pages=275–82}}</ref>
 
If a pregnant mother has high levels of interleukin-8, there is an increased risk of [[schizophrenia]] in her offspring.<ref name="pmid15121655">{{cite journal | vauthors = Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, Perrin M, Gorman JM, Susser ES | title = Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring | journal = Am J Psychiatry | volume = 161 | issue = 5 | pages = 889–95 | year = 2004 | pmid = 15121655 | doi = 10.1176/appi.ajp.161.5.889 }}</ref> High levels of Interleukin 8 have been shown to reduce the likelihood of positive responses to antipsychotic medication in schizophrenia.<ref name="pmid15291683">{{cite journal | vauthors = Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC | title = Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia | journal = J Clin Psychiatry | volume = 65 | issue = 7 | pages = 940–7 | year = 2004 | pmid = 15291683 | doi = 10.4088/JCP.v65n0710 }}</ref>
 
IL-8 has also been implicated in the pathology of cystic fibrosis. Through its action as a signalling molecule IL-8 is capable of recruiting and guiding neutrophils to the lung epithelium. Overstimulation and dysfunction of these recruited neutrophils within the airways results in release of a number of pro-inflammatory molecules and proteases resulting in further damage of lung tissue.<ref>{{cite journal | vauthors = Reeves EP, Williamson M, O'Neill SJ, Greally P, McElvaney NG | title = Nebulized hypertonic saline decreases IL-8 in sputum of patients with cystic fibrosis | journal = American Journal of Respiratory and Critical Care Medicine | volume = 183 | issue = 11 | pages = 1517–23 | date = Jun 2011 | pmid = 21330456 | doi = 10.1164/rccm.201101-0072oc }}</ref>
 
== Nomenclature ==
 
IL-8 was renamed CXCL8 by the Chemokine Nomenclature Subcommittee of the [[International Union of Immunological Societies]],.<ref name="pmid12433287">{{cite journal | vauthors = Bacon K, Baggiolini M, Broxmeyer H, Horuk R, Lindley I, Mantovani A, Maysushima K, Murphy P, Nomiyama H, Oppenheim J, Rot A, Schall T, Tsang M, Thorpe R, Van Damme J, Wadhwa M, Yoshie O, Zlotnik A, Zoon K | title = Chemokine/chemokine receptor nomenclature | journal = J. Interferon Cytokine Res. | volume = 22 | issue = 10 | pages = 1067–8 | year = 2002 | pmid = 12433287 | doi = 10.1089/107999002760624305 }}</ref> Its approved [[Human Genome Organisation|HUGO]] gene symbol is ''CXCL8''.
 
== Regulation of expression ==
 
The expression of IL-8 is negatively regulated by a number of mechanisms.  MiRNA-146a/b-5p indirectly represses IL-8 expression by silencing the expression of IRAK1.<ref name="pmid20148189">{{cite journal | vauthors = Bhaumik D, Scott GK, Schokrpur S, Patil CK, Orjalo AV, Rodier F, Lithgow GJ, Campisi J | title = MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8 | journal = Aging | volume = 1 | issue = 4 | pages = 402–11 | year = 2009 | pmid = 20148189 | pmc = 2818025 | doi =  }}</ref>  Additionally, the 3'UTR of IL-8 contains a A/U-rich element that makes it extremely unstable under certain conditions. IL-8 expression is also regulated by the transcription factor [[NF-κB]].<ref name="RottnerFreyssinet2009">{{cite journal | vauthors = Rottner M, Freyssinet JM, Martínez MC | title = Mechanisms of the noxious inflammatory cycle in cystic fibrosis | journal = Respir. Res. | volume = 10 | issue = 1 | pages = 23 | year = 2009 | pmid = 19284656 | doi = 10.1186/1465-9921-10-23 | pmc=2660284}}</ref> [[NF-κB]] regulation represents a novel anti-IL-8 therapy for use in inflammatory diseases such as cystic fibrosis.
 
== See also ==
* [[IL8RA|Interleukin 8 receptor, alpha]]
* [[IL8RA|Interleukin 8 receptor, alpha]]
* [[IL8RB|Interleukin 8 receptor, beta]]
* [[IL8RB|Interleukin 8 receptor, beta]]
{{Clear}}


==References==
== References ==
{{reflist|2}}
{{reflist|35em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|35em}}
{{PBB_Further_reading
* {{cite journal | vauthors = Baggiolini M, Clark-Lewis I | title = Interleukin-8, a chemotactic and inflammatory cytokine | journal = FEBS Lett. | volume = 307 | issue = 1 | pages = 97–101 | year = 1992 | pmid = 1639201 | doi = 10.1016/0014-5793(92)80909-Z }}
| citations =
* {{cite journal | vauthors = Wahl SM, Greenwell-Wild T, Hale-Donze H, Moutsopoulos N, Orenstein JM | title = Permissive factors for HIV-1 infection of macrophages | journal = J. Leukoc. Biol. | volume = 68 | issue = 3 | pages = 303–10 | year = 2000 | pmid = 10985244 | doi =  }}
*{{cite journal | author=Baggiolini M, Clark-Lewis I |title=Interleukin-8, a chemotactic and inflammatory cytokine. |journal=FEBS Lett. |volume=307 |issue= 1 |pages= 97-101 |year= 1992 |pmid= 1639201 |doi= }}
* {{cite journal | vauthors = Starckx S, Van den Steen PE, Wuyts A, Van Damme J, Opdenakker G | title = Neutrophil gelatinase B and chemokines in leukocytosis and stem cell mobilization | journal = Leuk. Lymphoma | volume = 43 | issue = 2 | pages = 233–41 | year = 2002 | pmid = 11999552 | doi = 10.1080/10428190290005982 }}
*{{cite journal | author=Wahl SM, Greenwell-Wild T, Hale-Donze H, ''et al.'' |title=Permissive factors for HIV-1 infection of macrophages. |journal=J. Leukoc. Biol. |volume=68 |issue= 3 |pages= 303-10 |year= 2000 |pmid= 10985244 |doi=  }}
* {{cite journal | vauthors = Smirnova MG, Kiselev SL, Gnuchev NV, Birchall JP, Pearson JP | title = Role of the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 and interleukin-8 in the pathogenesis of the otitis media with effusion | journal = Eur. Cytokine Netw. | volume = 13 | issue = 2 | pages = 161–72 | year = 2003 | pmid = 12101072 | doi =  }}
*{{cite journal | author=Starckx S, Van den Steen PE, Wuyts A, ''et al.'' |title=Neutrophil gelatinase B and chemokines in leukocytosis and stem cell mobilization. |journal=Leuk. Lymphoma |volume=43 |issue= 2 |pages= 233-41 |year= 2003 |pmid= 11999552 |doi= }}
* {{cite journal | vauthors = Struyf S, Proost P, Van Damme J | title = Regulation of the immune response by the interaction of chemokines and proteases | journal = Adv. Immunol. | volume = 81 | issue =  | pages = 1–44 | year = 2003 | pmid = 14711052 | doi = 10.1016/S0065-2776(03)81001-5 | isbn = 978-0-12-022481-4 | series = Advances in Immunology }}
*{{cite journal | author=Smirnova MG, Kiselev SL, Gnuchev NV, ''et al.'' |title=Role of the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 and interleukin-8 in the pathogenesis of the otitis media with effusion. |journal=Eur. Cytokine Netw. |volume=13 |issue= 2 |pages= 161-72 |year= 2003 |pmid= 12101072 |doi=  }}
* {{cite journal | vauthors = Chakravorty M, Ghosh A, Choudhury A, Santra A, Hembrum J, Roychoudhury S | title = Ethnic differences in allele distribution for the IL8 and IL1B genes in populations from eastern India | journal = Hum. Biol. | volume = 76 | issue = 1 | pages = 153–9 | year = 2004 | pmid = 15222686 | doi = 10.1353/hub.2004.0016 }}
*{{cite journal | author=Struyf S, Proost P, Van Damme J |title=Regulation of the immune response by the interaction of chemokines and proteases. |journal=Adv. Immunol. |volume=81 |issue=  |pages= 1-44 |year= 2004 |pmid= 14711052 |doi= }}
* {{cite journal | vauthors = Yuan A, Chen JJ, Yao PL, Yang PC | title = The role of interleukin-8 in cancer cells and microenvironment interaction | journal = Front. Biosci. | volume = 10 | issue =  | pages = 853–65 | year = 2005 | pmid = 15569594 | doi = 10.2741/1579 }}
*{{cite journal | author=Chakravorty M, Ghosh A, Choudhury A, ''et al.'' |title=Ethnic differences in allele distribution for the IL8 and IL1B genes in populations from eastern India. |journal=Hum. Biol. |volume=76 |issue= 1 |pages= 153-9 |year= 2004 |pmid= 15222686 |doi= }}
* {{cite journal | vauthors = Copeland KF | title = Modulation of HIV-1 transcription by cytokines and chemokines | journal = Mini Rev Med Chem | volume = 5 | issue = 12 | pages = 1093–101 | year = 2005 | pmid = 16375755 | doi = 10.2174/138955705774933383 }}
*{{cite journal | author=Yuan A, Chen JJ, Yao PL, Yang PC |title=The role of interleukin-8 in cancer cells and microenvironment interaction. |journal=Front. Biosci. |volume=10 |issue=  |pages= 853-65 |year= 2006 |pmid= 15569594 |doi= }}
*{{cite journal | author=Copeland KF |title=Modulation of HIV-1 transcription by cytokines and chemokines. |journal=Mini reviews in medicinal chemistry |volume=5 |issue= 12 |pages= 1093-101 |year= 2006 |pmid= 16375755 |doi= }}
}}
{{refend}}
{{refend}}


{{PDB Gallery|geneid=3576}}
{{Chemokines}}
{{Chemokines}}
{{interleukins}}
{{Chemokine receptor modulators}}
 
{{Interleukin receptor modulators}}
 
[[pl:Interleukina 8]]
[[zh:白细胞介素-8]]


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[[Category:Cytokines]]
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Revision as of 22:21, 26 October 2017

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Interleukin 8 (IL8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells[1] and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel-Palade bodies.[2][3] In humans, the interleukin-8 protein is encoded by the CXCL8 gene.[4] IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms.[5] In culture, a 72 amino acid peptide is the major form secreted by macrophages.[5]

There are many receptors on the surface membrane capable of binding IL-8; the most frequently studied types are the G protein-coupled serpentine receptors CXCR1 and CXCR2. Expression and affinity for IL-8 differs between the two receptors (CXCR1 > CXCR2). Through a chain of biochemical reactions, IL-8 is secreted and is an important mediator of the immune reaction in the innate immune system response.

Function

IL-8, also known as neutrophil chemotactic factor, has two primary functions. It induces chemotaxis in target cells, primarily neutrophils but also other granulocytes, causing them to migrate toward the site of infection. IL-8 also induces phagocytosis once they have arrived. IL-8 is also known to be a potent promoter of angiogenesis. In target cells, IL-8 induces a series of physiological responses required for migration and phagocytosis, such as increases in intracellular Ca2+, exocytosis (e.g. histamine release), and the respiratory burst.

IL-8 can be secreted by any cells with toll-like receptors that are involved in the innate immune response. Usually, it is the macrophages that see an antigen first, and thus are the first cells to release IL-8 to recruit other cells. Both monomer and homodimer forms of IL-8 have been reported to be potent inducers of the chemokine receptors CXCR1 and CXCR2. The homodimer is more potent, but methylation of Leu25 can block the activity of homodimers.

IL-8 is believed to play a role in the pathogenesis of bronchiolitis, a common respiratory tract disease caused by viral infection.[citation needed]

IL-8 is a member of the CXC chemokine family. The genes encoding this and the other ten members of the CXC chemokine family form a cluster in a region mapped to chromosome 4q.[4][6]

CXCL-8 mediated chemotaxis of the neutrophil

CXCL8 is the primary cytokine involved in the recruitment of neutrophils to the site of damage or infection; in a process called chemotaxis. A number of variables are essential for the successful chemotaxis of neutrophils, including the increased expression of high affinity adhesion molecules to secure the neutrophil to the endothelium near the affected site (and is therefore not washed away into the circulatory system), and that the neutrophil can digest its way through the basement membrane and the extracellular matrix (ECM) to reach affected site. CXCL8 plays a key role in inducing the cell signalling necessary to bring about these changes.[7]

Firstly, at the site of infection histamine release causes vasodilation of the capillaries near the injured area which slows down the blood flow in the region and encourages leukocytes, such as neutrophils, to come closer to the endothelium, and away from the centre of the lumen where the rate of blood flow is highest. Once this occurs weak interactions are made between the selectins expressed on the neutrophil and endothelial cells (expression of which is also increased through the action of CXCL8 and other cytokines). On the neutrophil these are: L selectins, and on the endothelial cell: P and E selectins. This causes the "rolling" phase of chemotaxis.

Once the neutrophil is rolling along the endothelium, it will come into contact with a CXCL8 molecule expressed on the surface which stimulates the cell signalling pathway, mediated through a G-coupled-protein-receptor. The binding of CXCL8 to CXCR1/2 on the neutrophil stimulates the neutrophils to upregulate their expression of the integrin, LFA-1, which takes part in high affinity bonding with ICAM-1 receptors expressed on the endothelium. The expression and affinity of LFA-1 is significantly increased to maximise binding. This causes the neutrophil to slow down more until it is stationary. Another key function of the cell signalling stimulated by CXCL8, is the initiation of the oxidative burst. This process allows the build up of proteolytic enzymes and reactive oxygen species (ROS) which are necessary to break down the ECM and basement membrane. These are released in secretory granules, along with more integrins. The release of ROS and damaging enzymes is regulated to minimise host damage, but continues to reach site of infection at which it will carry out its effector functions.[7]

Target cells

While neutrophil granulocytes are the primary target cells of IL-8, there are a relatively wide range of cells (endothelial cells, macrophages, mast cells, and keratinocytes) that respond to this chemokine. The chemoattractant activity of IL-8 in similar concentrations to vertebrates was proven in Tetrahymena pyriformis, which suggests a phylogenetically well-conserved structure and function for this chemokine.[8]

Clinical significance

Interleukin-8 is a key mediator associated with inflammation where it plays a key role in neutrophil recruitment and neutrophil degranulation.[9] As an example, it has been cited as a proinflammatory mediator in gingivitis[10] and psoriasis.

Interleukin-8 secretion is increased by oxidant stress, which thereby cause the recruitment of inflammatory cells and induces a further increase in oxidant stress mediators, making it a key parameter in localized inflammation.[11] IL-8 was shown to be associated with obesity.[12]

IL-8 has also been implied to have a role in colorectal cancer by acting as an autocrine growth factor for colon carcinoma cell lines[13] or the promotion of division and possible migration by cleaving metalloproteinase molecules.[14]

If a pregnant mother has high levels of interleukin-8, there is an increased risk of schizophrenia in her offspring.[15] High levels of Interleukin 8 have been shown to reduce the likelihood of positive responses to antipsychotic medication in schizophrenia.[16]

IL-8 has also been implicated in the pathology of cystic fibrosis. Through its action as a signalling molecule IL-8 is capable of recruiting and guiding neutrophils to the lung epithelium. Overstimulation and dysfunction of these recruited neutrophils within the airways results in release of a number of pro-inflammatory molecules and proteases resulting in further damage of lung tissue.[17]

Nomenclature

IL-8 was renamed CXCL8 by the Chemokine Nomenclature Subcommittee of the International Union of Immunological Societies,.[18] Its approved HUGO gene symbol is CXCL8.

Regulation of expression

The expression of IL-8 is negatively regulated by a number of mechanisms. MiRNA-146a/b-5p indirectly represses IL-8 expression by silencing the expression of IRAK1.[19] Additionally, the 3'UTR of IL-8 contains a A/U-rich element that makes it extremely unstable under certain conditions. IL-8 expression is also regulated by the transcription factor NF-κB.[20] NF-κB regulation represents a novel anti-IL-8 therapy for use in inflammatory diseases such as cystic fibrosis.

See also

References

  1. ↑ Hedges JC, Singer CA, Gerthoffer WT (2000). "Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes". Am. J. Respir. Cell Mol. Biol. 23 (1): 86–94. doi:10.1165/ajrcmb.23.1.4014. PMID 10873157.
  2. ↑ Wolff B, Burns AR, Middleton J, Rot A (1998). "Endothelial cell "memory" of inflammatory stimulation: human venular endothelial cells store interleukin 8 in Weibel-Palade bodies". J. Exp. Med. 188 (9): 1757–62. doi:10.1084/jem.188.9.1757. PMC 2212526. PMID 9802987.
  3. ↑ Utgaard JO, Jahnsen FL, Bakka A, Brandtzaeg P, Haraldsen G (1998). "Rapid secretion of prestored interleukin 8 from Weibel-Palade bodies of microvascular endothelial cells". J. Exp. Med. 188 (9): 1751–6. doi:10.1084/jem.188.9.1751. PMC 2212514. PMID 9802986.
  4. ↑ 4.0 4.1 Modi WS, Dean M, Seuanez HN, Mukaida N, Matsushima K, O'Brien SJ (1990). "Monocyte-derived neutrophil chemotactic factor (MDNCF/IL-8) resides in a gene cluster along with several other members of the platelet factor 4 gene superfamily". Hum. Genet. 84 (2): 185–7. doi:10.1007/BF00208938. PMID 1967588.
  5. ↑ 5.0 5.1 Brat DJ, Bellail AC, Van Meir EG (2005). "The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis". Neuro-oncology. 7 (2): 122–133. doi:10.1215/s1152851704001061.
  6. ↑ "Entrez Gene: IL8 interleukin 8".
  7. ↑ 7.0 7.1 Dixit N, Simon SI (2012). "Chemokines, selectins and intracellular calcium flux: temporal and spatial cues for leukocyte arrest". Frontiers in Immunology. 3: 188. doi:10.3389/fimmu.2012.00188. PMC 3392659. PMID 22787461.
  8. ↑ Köhidai L, Csaba G (1998). "Chemotaxis and chemotactic selection induced with cytokines (IL-8, RANTES and TNF-alpha) in the unicellular Tetrahymena pyriformis". Cytokine. 10 (7): 481–6. doi:10.1006/cyto.1997.0328. PMID 9702410.
  9. ↑ Harada A, Sekido N, Akahoshi T, Wada T, Mukaida N, Matsushima K (Nov 1994). "Essential involvement of interleukin-8 (IL-8) in acute inflammation". Journal of Leukocyte Biology. 56 (5): 559–64. PMID 7964163.
  10. ↑ Haake, SK, Huang, GTJ: Molecular Biology of the host-Microbe Interaction in Periodontal Diseases (Selected Topics). In Newman, Takei, Carranza, editors: Clinical Periodontology, 9th Edition. Philadelphia: W.B.Saunders Co. 2002. page 162.
  11. ↑ Vlahopoulos S, Boldogh I, Casola A, Brasier AR (1999). "Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation". Blood. 94 (6): 1878–89. PMID 10477716.
  12. ↑ Sharabiani MT, Vermeulen R, Scoccianti C, Hosnijeh FS, Minelli L, Sacerdote C, Palli D, Krogh V, Tumino R, Chiodini P, Panico S, Vineis P (2011). "Immunologic profile of excessive body weight". Biomarkers. 16 (3): 243–51. doi:10.3109/1354750X.2010.547948. PMID 21506696.
  13. ↑ Brew R, Erikson JS, West DC, Kinsella AR, Slavin J, Christmas SE (2000). "Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitro". Cytokine. 12 (1): 78–85. doi:10.1006/cyto.1999.0518. PMID 10623446.
  14. ↑ Itoh Y, Joh T, Tanida S, Sasaki M, Kataoka H, Itoh K, Oshima T, Ogasawara N, Togawa S, Wada T, Kubota H, Mori Y, Ohara H, Nomura T, Higashiyama S, Itoh M (2005). "IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in human colon carcinoma cells". Cytokine. 29 (6): 275–82. doi:10.1016/j.cyto.2004.11.005. PMID 15749028.
  15. ↑ Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, Perrin M, Gorman JM, Susser ES (2004). "Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring". Am J Psychiatry. 161 (5): 889–95. doi:10.1176/appi.ajp.161.5.889. PMID 15121655.
  16. ↑ Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC (2004). "Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia". J Clin Psychiatry. 65 (7): 940–7. doi:10.4088/JCP.v65n0710. PMID 15291683.
  17. ↑ Reeves EP, Williamson M, O'Neill SJ, Greally P, McElvaney NG (Jun 2011). "Nebulized hypertonic saline decreases IL-8 in sputum of patients with cystic fibrosis". American Journal of Respiratory and Critical Care Medicine. 183 (11): 1517–23. doi:10.1164/rccm.201101-0072oc. PMID 21330456.
  18. ↑ Bacon K, Baggiolini M, Broxmeyer H, Horuk R, Lindley I, Mantovani A, Maysushima K, Murphy P, Nomiyama H, Oppenheim J, Rot A, Schall T, Tsang M, Thorpe R, Van Damme J, Wadhwa M, Yoshie O, Zlotnik A, Zoon K (2002). "Chemokine/chemokine receptor nomenclature". J. Interferon Cytokine Res. 22 (10): 1067–8. doi:10.1089/107999002760624305. PMID 12433287.
  19. ↑ Bhaumik D, Scott GK, Schokrpur S, Patil CK, Orjalo AV, Rodier F, Lithgow GJ, Campisi J (2009). "MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8". Aging. 1 (4): 402–11. PMC 2818025. PMID 20148189.
  20. ↑ Rottner M, Freyssinet JM, Martínez MC (2009). "Mechanisms of the noxious inflammatory cycle in cystic fibrosis". Respir. Res. 10 (1): 23. doi:10.1186/1465-9921-10-23. PMC 2660284. PMID 19284656.

Further reading

  • Baggiolini M, Clark-Lewis I (1992). "Interleukin-8, a chemotactic and inflammatory cytokine". FEBS Lett. 307 (1): 97–101. doi:10.1016/0014-5793(92)80909-Z. PMID 1639201.
  • Wahl SM, Greenwell-Wild T, Hale-Donze H, Moutsopoulos N, Orenstein JM (2000). "Permissive factors for HIV-1 infection of macrophages". J. Leukoc. Biol. 68 (3): 303–10. PMID 10985244.
  • Starckx S, Van den Steen PE, Wuyts A, Van Damme J, Opdenakker G (2002). "Neutrophil gelatinase B and chemokines in leukocytosis and stem cell mobilization". Leuk. Lymphoma. 43 (2): 233–41. doi:10.1080/10428190290005982. PMID 11999552.
  • Smirnova MG, Kiselev SL, Gnuchev NV, Birchall JP, Pearson JP (2003). "Role of the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 and interleukin-8 in the pathogenesis of the otitis media with effusion". Eur. Cytokine Netw. 13 (2): 161–72. PMID 12101072.
  • Struyf S, Proost P, Van Damme J (2003). "Regulation of the immune response by the interaction of chemokines and proteases". Adv. Immunol. Advances in Immunology. 81: 1–44. doi:10.1016/S0065-2776(03)81001-5. ISBN 978-0-12-022481-4. PMID 14711052.
  • Chakravorty M, Ghosh A, Choudhury A, Santra A, Hembrum J, Roychoudhury S (2004). "Ethnic differences in allele distribution for the IL8 and IL1B genes in populations from eastern India". Hum. Biol. 76 (1): 153–9. doi:10.1353/hub.2004.0016. PMID 15222686.
  • Yuan A, Chen JJ, Yao PL, Yang PC (2005). "The role of interleukin-8 in cancer cells and microenvironment interaction". Front. Biosci. 10: 853–65. doi:10.2741/1579. PMID 15569594.
  • Copeland KF (2005). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini Rev Med Chem. 5 (12): 1093–101. doi:10.2174/138955705774933383. PMID 16375755.
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