View source for Biology:Interleukin 8

{{Short description|Mammalian protein found in Homo sapiens}}
{{Infobox_gene}}
'''Interleukin 8''' ('''IL-8''' or chemokine (C-X-C motif) ligand 8, '''CXCL8''') is a [[Biology:Chemokine|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 | citeseerx = 10.1.1.326.6212 }}</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 [[Biology:Protein|protein]] is encoded by the ''CXCL8'' [[Biology:Gene|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 | s2cid = 2217894 }}</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 |vauthors=Brat DJ, Bellail AC, Van Meir EG | year = 2005 | title = The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis | journal = Neuro-Oncology | volume = 7 | issue = 2| pages = 122–133 | doi=10.1215/s1152851704001061| pmid = 15831231 | pmc = 1871893}}</ref> In culture, a 72 amino acid peptide is the major form secreted by macrophages.<ref name="Brat DJ 2005. pages 122-133"/>

There are many receptors on the surface membrane capable of binding IL-8; the most frequently studied types are the [[Biology:G protein-coupled receptor|G protein-coupled]] serpentine receptors [[Biology:Interleukin 8 receptor, alpha|CXCR1]] and [[Biology: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.

== Function ==
IL-8, also known as ''neutrophil chemotactic factor'', has two primary functions.  It induces [[Physics:Chemotaxis|chemotaxis]] in target cells, primarily neutrophils but also other granulocytes, causing them to migrate toward the site of infection. IL-8 also stimulates phagocytosis once they have arrived.  IL-8 is also known to be a potent promoter of [[Biology:Angiogenesis|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. [[Chemistry:Histamine|histamine]] release), and the [[Biology:Respiratory burst|respiratory burst]].

IL-8 can be secreted by any cells with [[Biology:Toll-like receptor|toll-like receptor]]s that are involved in the innate immune response and has been demonstrated to be a signatory chemokine of CR2+ naive T cells, also known as recent thymic emigrants.<ref>{{cite journal|vauthors=Pekalski ML, García AR, Ferreira RC, Rainbow DB, Smyth DJ, Mashar M, Brady J, Savinykh N, Dopico XC, Mahmood S, Duley S, Stevens HE, Walker NM, Cutler AJ, Waldron-Lynch F, Dunger DB, Shannon-Lowe C, Coles AJ, Jones JL, Wallace C, Todd JA, Wicker LS |title=Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2 |journal=JCI Insight |volume=2 |issue=16 |date=August 2017 |pmid=28814669 |pmc=5621870 |doi=10.1172/jci.insight.93739}}</ref> 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 [[Biology:Methylation|methylation]] of Leu25 can block the activity of homodimers.

IL-8 is believed to play a role in the pathogenesis of [[Medicine:Bronchiolitis|bronchiolitis]], a common respiratory tract disease caused by viral infection.{{citation needed|date=May 2017}}

IL-8 is a member of the [[Biology: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}}</ref>

== CXCL-8 mediated chemotaxis of the neutrophil ==
CXCL8 is the primary [[Biology:Cytokine|cytokine]] involved in the recruitment of neutrophils to the site of damage or infection; in a process called [[Physics:Chemotaxis|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 | pages = 188 | year = 2012 | pmid = 22787461 | pmc = 3392659 | doi = 10.3389/fimmu.2012.00188 | doi-access = free }}</ref>

Firstly, at the site of infection [[Chemistry:Histamine|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 [[Biology:Integrin|integrin]], LFA-1, which takes part in high affinity bonding with [[Biology:ICAM-1|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.<ref name="Dixit_2012" />

== Target cells ==

While neutrophil granulocytes are the primary target cells of IL-8, there are a relatively wide range of cells (endothelial cells, [[Biology:Macrophage|macrophage]]s, [[Biology:Mast cell|mast cell]]s, and [[Biology:Keratinocyte|keratinocyte]]s) that respond to this chemokine. The chemoattractant activity of IL-8 in similar concentrations to vertebrates was proven in ''[[Biology:Tetrahymena|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 | s2cid = 33755476 }}</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 | archive-url = https://archive.today/20160727021201/http://www.jleukbio.org/content/56/5/559 | url-status = dead | archive-date = 2016-07-27 | doi = 10.1002/jlb.56.5.559 | s2cid = 8035653 }}</ref> As an example, it has been cited as a proinflammatory mediator in [[Medicine:Gingivitis|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 [[Medicine:Psoriasis|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 =  10.1182/blood.V94.6.1878.418k03_1878_1889| s2cid = 25974629 }}</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 | s2cid = 36127785 }}</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 [[Biology:Metalloproteinase|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> It has also been shown that IL-8 plays an important role in chemoresistance of malignant pleural mesothelioma by inducing expression of transmembrane transporters.<ref>Milosevic, V. et al. Wnt/IL-1β/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5.Int. J. Cancer, https://doi.org/10.1002/ijc.32419</ref>

If a pregnant mother has high levels of interleukin-8, there is an increased risk of [[Medicine:Schizophrenia|schizophrenia]] in her offspring.<ref name="pmid15121655">{{cite journal | vauthors = Brown AS, Hooton J, Schaefer CA, Zhang H, [[Biography:Eva Petkova|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>

Some benzodiazepines have inhibitory effects on the [[Biology:Adenosine A2B receptor|adenosine A2B receptor]] mediated secretion of interleukin-8 in human mast cells. In a 2013 study, [[Chemistry:Diazepam|diazepam]], 4′-chlorodiazepam and [[Chemistry:Flunitrazepam|flunitrazepam]] markedly reduced NECA-induced interleukin-8 production in that order of potency, whereas [[Chemistry:Clonazepam|clonazepam]] showed only a modest inhibition.<ref>{{cite journal | vauthors = Hoffmann K, Xifró RA, Hartweg JL, Spitzlei P, Meis K, Molderings GJ, von Kügelgen I | title = Inhibitory effects of benzodiazepines on the adenosine A(2B) receptor mediated secretion of interleukin-8 in human mast cells. | journal = Eur J Pharmacol | date = Jan 2013 | volume = 700 | issue = 1–3 | pages = 152–8 | pmid = 23266380 | doi = 10.1016/j.ejphar.2012.12.003 }}</ref>

== 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 [[Biology:IRAK1|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 =  10.18632/aging.100042}}</ref>  Additionally, the 3'UTR of IL-8 contains a A/U-rich element that makes it extremely unstable under certain conditions. IL-8 and other [[Biology:Inflammatory cytokine|inflammatory cytokine]]s form a [[Finance:Virtuous circle and vicious circle|vicious cycle]] with the transcription factor [[Biology:NF-κB|NF-κB]] in [[Medicine:Cystic fibrosis|cystic fibrosis]].<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 | doi-access = free }}</ref> [[Biology:NF-κB|NF-κB]] regulation represents a novel anti-IL-8 therapy for use in inflammatory diseases such as cystic fibrosis. Pathways leading to the induction of ribosomal protein S6 (rpS6) phosphorylation have also been found to enhance IL-8 protein synthesis. This translational control of IL-8 expression is dependent on A/U-rich proximal sequences (APS), which are found in the 3'UTR of IL-8 immediately after the stop codon.<ref name="pmid25633224">{{cite journal | vauthors = Ang Z, Abdi Gunawan Koen R, Er JZ, Lee LT, Tam Kit Chung J, Guo H, Ding JL | title = Novel AU-rich proximal UTR sequences (APS) enhance CXCL8 synthesis upon the induction of rpS6 phosphorylation. | journal = PLOS Genet. | year = 2019 | pmid = 30969964 | doi=10.1371/journal.pgen.1008077 | volume=15 | issue = 4 | pmc=6476525 | page=e1008077 | doi-access = free }}</ref>

== Nomenclature ==

IL-8 was renamed CXCL8 by the Chemokine Nomenclature Subcommittee of the [[Organization:International Union of Immunological Societies|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, [[Biography:Meenakshi Wadhwa|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 [[Organization:Human Genome Organisation|HUGO]] gene symbol is ''CXCL8''. Its receptors were similarly renamed: 
* Interleukin 8 receptor, alpha — CXCR1
* Interleukin 8 receptor, beta — CXCR2

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

== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Milosevic V et al | title = Wnt/IL-1β/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5 | journal = Int. J. Cancer | volume = 146 | issue = 1 | pages = 192–207 | date = January 2020 | doi = 10.1002/ijc.32419 | pmid = 31107974 | hdl = 2318/1711962 | s2cid = 160014053 | url = https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32419 | hdl-access = free }}
* {{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| s2cid = 10615150 | doi-access = free }}
* {{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 | doi = 10.1189/jlb.68.3.303 | pmid = 10985244 | s2cid = 41684404 }}
* {{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| s2cid = 940921 }}
* {{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 }}
* {{cite book | vauthors = Struyf S, Proost P, Van Damme J | title = Regulation of the Immune Response by the Interaction of Chemokines and Proteases | volume = 81 | 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 | 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| s2cid = 2816300 }}
* {{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 =  1–3| pages = 853–65 | year = 2005 | pmid = 15569594 | doi = 10.2741/1579| s2cid = 13377783 | doi-access = free }}
* {{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}}
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[[Category:Cytokines]]

{{Sourceattribution|Interleukin 8}}