Interleukin 8

Chemokine (C-X-C motif) ligand 8
PDB rendering based on 1IL8.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1ICW​, 1IKL​, 1IKM​, 1IL8​, 1ILP​, 1ILQ​, 1QE6​, 1ROD​, 2IL8​, 3IL8​
Identifiers
Symbols	CXCL8 ; GCP-1; GCP1; IL8; LECT; LUCT; LYNAP; MDNCF; MONAP; NAF; NAP-1; NAP1
External IDs	OMIM: 146930 HomoloGene: 47937 ChEMBL: 2157 GeneCards: CXCL8 Gene
Gene ontology Molecular function • interleukin-8 receptor binding • protein binding • chemokine activity Cellular component • extracellular region • extracellular space • intracellular Biological process • angiogenesis • response to molecule of bacterial origin • movement of cell or subcellular component • chemotaxis • inflammatory response • immune response • cell cycle arrest • signal transduction • G-protein coupled receptor signaling pathway • negative regulation of cell proliferation • calcium-mediated signaling • regulation of cell adhesion • neutrophil chemotaxis • endoplasmic reticulum unfolded protein response • receptor internalization • response to endoplasmic reticulum stress • intracellular signal transduction • PERK-mediated unfolded protein response • neutrophil activation • cellular protein metabolic process • cellular response to fibroblast growth factor stimulus • regulation of single stranded viral RNA replication via double stranded DNA intermediate • negative regulation of G-protein coupled receptor protein signaling pathway • positive regulation of angiogenesis • embryonic digestive tract development • induction of positive chemotaxis • chemokine-mediated signaling pathway • cellular response to lipopolysaccharide • cellular response to interleukin-1 • cellular response to tumor necrosis factor • positive regulation of neutrophil chemotaxis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3576	n/a
Ensembl	ENSG00000169429	n/a
UniProt	P10145	n/a
RefSeq (mRNA)	NM_000584	n/a
RefSeq (protein)	NP_000575	n/a
Location (UCSC)	Chr 4: 73.74 – 73.74 Mb	n/a
PubMed search		n/a

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 IL8 gene.^[4] IL-8 is initially produced as a precursor peptide of 99 amino acids long 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.{fact}

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]

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.^[7]

Clinical significance

Interleukin-8 is a key mediator associated with inflammation where it plays a key role in neutrophil recruitment and neutrophil degranulation.^[8] As an example, it has been cited as a proinflammatory mediator in gingivitis^[9] 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.^[10] IL-8 was shown to be associated with obesity.^[11]

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^[12] or the promotion of division and possible migration by cleaving metalloproteinase molecules.^[13]

If a pregnant mother has high levels of interleukin-8, there is an increased risk of schizophrenia in her offspring.^[14] High levels of Interleukin 8 have been shown to reduce the likelihood of positive responses to antipsychotic medication in schizophrenia.^[15]

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.^[16]

Nomenclature

IL-8 was renamed CXCL8 by the Chemokine Nomenclature Subcommittee of the International Union of Immunological Societies,.^[17] 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.^[18] 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.^[19] NF-κB regulation represents a novel anti-IL-8 therapy for use in inflammatory diseases such as cystic fibrosis.

See also

• Interleukin 8 receptor, alpha
• Interleukin 8 receptor, beta

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. 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. Brat DJ, Bellail AC, and Van Meir EG. 2005. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-oncology. 7(2), pages 122-133
6. "Entrez Gene: IL8 interleukin 8".
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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). doi:10.1016/j.cyto.2004.11.005. PMID 15749028.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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 (Albany NY) 1 (4): 402–11. PMC: 2818025. PMID 20148189.
19. 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. 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.