Interleukin 8

IL-8, also known as monocyte-derived neutrophil chemotactic factor (MDNCF),{{cite journal | vauthors = Matsushima K, Shichino S, Ueha S | title = Thirty-five years since the discovery of chemotactic cytokines, interleukin-8 and MCAF: A historical overview | journal = Proceedings of the Japan Academy. Series B, Physical and Biological Sciences | volume = 99 | issue = 7 | pages = 213–226 | date = 31 July 2023 | pmid = 37518010 | pmc = 10700015 | doi = 10.2183/pjab.99.014 | bibcode = 2023PJAB...99..213M }} 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 stimulates 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 and has been demonstrated to be a signatory chemokine of CR2+ naive T cells, also known as recent thymic emigrants.{{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 }}{{cite journal | vauthors = van den Broek T, Delemarre EM, Janssen WJ, Nievelstein RA, Broen JC, Tesselaar K, Borghans JA, Nieuwenhuis EE, Prakken BJ, Mokry M, Jansen NJ, van Wijk F | title = Neonatal thymectomy reveals differentiation and plasticity within human naive T cells | journal = The Journal of Clinical Investigation | volume = 126 | issue = 3 | pages = 1126–1136 | date = March 2016 | pmid = 26901814 | pmc = 4767338 | doi = 10.1172/JCI84997 }}{{cite journal | vauthors = Das A, Rouault-Pierre K, Kamdar S, Gomez-Tourino I, Wood K, Donaldson I, Mein CA, Bonnet D, Hayday AC, Gibbons DL | title = Adaptive from Innate: Human IFN-γ⁺CD4⁺ T Cells Can Arise Directly from CXCL8-Producing Recent Thymic Emigrants in Babies and Adults | journal = Journal of Immunology | volume = 199 | issue = 5 | pages = 1696–1705 | date = September 2017 | pmid = 28754679 | pmc = 5563168 | doi = 10.4049/jimmunol.1700551 }} 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 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.

Another key function of the cell signalling stimulated by IL-8, is the initiation of the oxidative burst.{{cite journal | vauthors = Bréchard S, Bueb JL, Tschirhart EJ | title = Interleukin-8 primes oxidative burst in neutrophil-like HL-60 through changes in cytosolic calcium | journal = Cell Calcium | volume = 37 | issue = 6 | pages = 531–540 | date = June 2005 | pmid = 15862344 | doi = 10.1016/j.ceca.2005.01.019 }} 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.{{cite web | title = Entrez Gene: IL8 interleukin 8| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3576}}

IL-8 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. IL-8 plays a key role in inducing the cell signalling necessary to bring about these changes.{{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 }}

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 IL-8 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 IL-8 molecule expressed on the surface which stimulates the cell signalling pathway, mediated through a G-coupled-protein-receptor. The binding of IL-8 to CXCR1/2 on the neutrophil stimulates the neutrophils to upregulate their expression of the integrin, LFA-1 (Lymphocyte function-associated antigen 1), which takes part in high affinity bonding with ICAM-1(Intercellular Adhesion Molecule 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.

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.{{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 = 481–486 | date = July 1998 | pmid = 9702410 | doi = 10.1006/cyto.1997.0328 | s2cid = 33755476 }}

Interleukin-8 is a key mediator associated with inflammation where it plays a key role in neutrophil recruitment and neutrophil degranulation.{{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 = 559–564 | date = November 1994 | pmid = 7964163 | doi = 10.1002/jlb.56.5.559 | url = http://www.jleukbio.org/content/56/5/559 | url-status = dead | s2cid = 8035653 | archive-url = https://archive.today/20160727021201/http://www.jleukbio.org/content/56/5/559 | archive-date = 2016-07-27 }} As an example, it has been cited as a proinflammatory mediator in gingivitisHaake, 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. and psoriasis.

IL-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.{{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 = 1878–1889 | date = September 1999 | pmid = 10477716 | doi = 10.1182/blood.V94.6.1878.418k03_1878_1889 | s2cid = 25974629 }} IL-8 was shown to be associated with obesity.{{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 = 243–251 | date = May 2011 | pmid = 21506696 | doi = 10.3109/1354750X.2010.547948 | s2cid = 36127785 }}

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{{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 | date = January 2000 | pmid = 10623446 | doi = 10.1006/cyto.1999.0518 }} or the promotion of division and possible migration by cleaving metalloproteinase molecules.{{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 | pages = 275–282 | date = March 2005 | pmid = 15749028 | doi = 10.1016/j.cyto.2004.11.005 }} It has also been shown that IL-8 plays an important role in chemoresistance of malignant pleural mesothelioma by inducing expression of transmembrane transporters.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

If a pregnant mother has high levels of IL-8, there is an increased risk of schizophrenia in her offspring.{{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 = The American Journal of Psychiatry | volume = 161 | issue = 5 | pages = 889–895 | date = May 2004 | pmid = 15121655 | doi = 10.1176/appi.ajp.161.5.889 }} High levels of Interleukin 8 have been shown to reduce the likelihood of positive responses to antipsychotic medication in schizophrenia.{{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 = The Journal of Clinical Psychiatry | volume = 65 | issue = 7 | pages = 940–947 | date = July 2004 | pmid = 15291683 | doi = 10.4088/JCP.v65n0710 }}

Elevated cerebrospinal fluid (CSF) levels of IL-8 have been observed in individuals with schizophrenia, schizophrenia spectrum disorders, bipolar disorder, major depressive disorder, autism spectrum disorder, Parkinson’s disease, dementia, and multiple sclerosis.{{cite journal | vauthors = Shkundin A, Halaris A | title = IL-8 (CXCL8) Correlations with Psychoneuroimmunological Processes and Neuropsychiatric Conditions | journal = Journal of Personalized Medicine | volume = 14 | issue = 5 | pages = 488 | date = May 2024 | pmid = 38793070 | pmc = 11122344 | doi = 10.3390/jpm14050488 | doi-access = free }} In contrast, CSF IL-8 levels are significantly lower in individuals who have attempted suicide and show a negative correlation with anxiety symptoms in suicide attempters.

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.{{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 = 1517–1523 | date = June 2011 | pmid = 21330456 | doi = 10.1164/rccm.201101-0072oc }}

Some benzodiazepines have inhibitory effects on the adenosine A2B receptor mediated secretion of IL-8 in human mast cells. In a 2013 study, diazepam, 4′-chlorodiazepam and flunitrazepam markedly reduced NECA-induced IL-8 production in that order of potency, whereas clonazepam showed only a modest inhibition.{{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 = European Journal of Pharmacology | volume = 700 | issue = 1-3 | pages = 152–158 | date = January 2013 | pmid = 23266380 | doi = 10.1016/j.ejphar.2012.12.003 }}

An increase in IL-8 levels has also been observed in relation to bronchiolitis, a common respiratory tract disease caused by viral infection.{{cite journal | vauthors = Bohmwald K, Gálvez NM, Canedo-Marroquín G, Pizarro-Ortega MS, Andrade-Parra C, Gómez-Santander F, Kalergis AM | title = Contribution of Cytokines to Tissue Damage During Human Respiratory Syncytial Virus Infection | journal = Frontiers in Immunology | volume = 10 | pages = 452 | date = 18 March 2019 | pmid = 30936869 | pmc = 6431622 | doi = 10.3389/fimmu.2019.00452 | doi-access = free }}{{cite journal | vauthors = Sacco RE, McGill JL, Palmer MV, Lippolis JD, Reinhardt TA, Nonnecke BJ | title = Neonatal calf infection with respiratory syncytial virus: drawing parallels to the disease in human infants | journal = Viruses | volume = 4 | issue = 12 | pages = 3731–3753 | date = December 2012 | pmid = 23342375 | pmc = 3528288 | doi = 10.3390/v4123731 | doi-access = free }}

== Modulators of CXCL8 ==

The production and release of CXCL8 (IL-8) can be influenced by multiple factors that regulate its expression and levels. Several cytokines and biochemical substances act as inducers of IL-8, including IL-1α, IL-1β, IL-7, IL-17, IL-22, tumor necrosis factor-alpha (TNF-α), histamine, stromal cell-derived factor-1 (SDF-1, CXCL12), lipopolysaccharides (LPSs), reactive oxygen species (ROS), cadmium (Cd), phytohemagglutinin (PHA), prostaglandin E2 (PGE2), polyinosinic-polycytidylic acid (poly I:C), concanavalin A (ConA), NaCl, thrombin, all-trans-retinoic acid (ATRA), and various other cellular stressors.

Conversely, several cytokines and compounds demonstrate the ability to reduce IL-8 levels, including IL-4, IL-10, IL-35, transforming growth factor-beta 1 (TGF-β1), interferon-alpha (IFN-α), interferon-beta (IFN-β), glucocorticoids (GCs), lipoxins, vitamin D, lipoxygenase (LOX) inhibitors, antcin K, tannins, glycyrrhizin (GL), and N-acetylcysteine (NAC).

The impact of these modulators on IL-8 levels is dependent on factors such as their concentration, duration of exposure, and the specific cellular context.

== Regulation of CXCL8 expression ==

The CXCL8 gene is located on chromosome 4q13-21 and consists of four exons and three introns, featuring a unique CAT- and TATA-like structure. The proximal promoter region, containing approximately 200 nucleotides within the 5′-flanking region, plays a significant role in transcriptional regulation of CXCL8. Notably, this 5′-flanking region differs significantly from other cytokine and acute-phase reactant genes.

In resting cells, CXCL8 is present at extremely low levels, making it difficult to detect. However, the expression of CXCL8 is induced by a range of factors and stressors, with transcription factors NF-κB and activator protein-1 (AP-1) playing key roles in mediating this response. This induction results in a significant increase in CXCL8 expression, typically ranging from 10- to 100-fold. IL-8 and other inflammatory cytokines form a vicious cycle with NF-κB.{{cite journal | vauthors = Rottner M, Freyssinet JM, Martínez MC | title = Mechanisms of the noxious inflammatory cycle in cystic fibrosis | journal = Respiratory Research | volume = 10 | issue = 1 | pages = 23 | date = March 2009 | pmid = 19284656 | pmc = 2660284 | doi = 10.1186/1465-9921-10-23 | doi-access = free }}

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 AU-rich proximal sequences (APS), which are found in the 3' untranslated region (3' UTR) of IL-8 immediately after the stop codon. The 3' UTR of CXCL8 also contains adenylate-uridylate-rich elements (AREs), which accelerate mRNA degradation.{{cite journal | vauthors = Ang Z, Koean RA, Er JZ, Lee LT, Tam JK, Guo H, Ding JL | title = Novel AU-rich proximal UTR sequences (APS) enhance CXCL8 synthesis upon the induction of rpS6 phosphorylation | journal = PLoS Genetics | volume = 15 | issue = 4 | pages = e1008077 | date = April 2019 | pmid = 30969964 | pmc = 6476525 | doi = 10.1371/journal.pgen.1008077 | doi-access = free }}

Additionally, MicroRNA-146a-5p (miR-146a-5p) indirectly represses IL-8 expression by silencing IRAK1.{{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 = 402–411 | date = April 2009 | pmid = 20148189 | pmc = 2818025 | doi = 10.18632/aging.100042 }} Among multiple microRNAs (miRs), miR-146a-5p has been identified as an anti-inflammatory regulator targeting signal molecules in the NF-κB pathway.{{cite journal | vauthors = Lo WY, Wang SJ, Wang HJ | title = Non-canonical Interaction Between O-Linked N-Acetylglucosamine Transferase and miR-146a-5p Aggravates High Glucose-Induced Endothelial Inflammation | journal = Frontiers in Physiology | volume = 11 | pages = 1091 | date = October 30, 2020 | pmid = 33192537 | pmc = 7662465 | doi = 10.3389/fphys.2020.01091 | doi-access = free }}

Notably, genetic polymorphisms in the CXCL8 gene can influence its transcriptional activity, potentially altering IL-8 production and contributing to variations in disease susceptibility, progression, and severity among individuals.

IL-8 was renamed CXCL8 by the Chemokine Nomenclature Subcommittee of the International Union of Immunological Societies,.{{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 = Journal of Interferon & Cytokine Research | volume = 22 | issue = 10 | pages = 1067–1068 | date = October 2002 | pmid = 12433287 | doi = 10.1089/107999002760624305 }} Its approved HUGO gene symbol is CXCL8. Its receptors were similarly renamed:

• Interleukin 8 receptor, alpha — CXCR1
• Interleukin 8 receptor, beta — CXCR2

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Category:Cytokines